[7,6]-fused bicyclic antidiabetic compounds

ABSTRACT

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of Chinese PCT Application No. PCT/CN15/086108, filed on Aug. 5,2015, which claims priority from and the benefit of Chinese PCT PatentApplication No. PCT/CN14/084034, filed Aug. 8, 2014.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disease derived from multiple causative factorsand characterized by elevated levels of plasma glucose (hyperglycemia)in the fasting state or after administration of glucose during an oralglucose tolerance test. There are two generally recognized forms ofdiabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), patients produce little or no insulin, the hormone whichregulates glucose utilization. In Type 2 diabetes, ornoninsulin-dependent diabetes mellitus (NIDDM), insulin is stillproduced in the body, however patients have a resistance to the effectsof insulin in stimulating glucose and lipid metabolism in theinsulin-sensitive muscle, liver and adipose tissues. Type 2 diabetespatients often have normal levels of insulin, and may havehyperinsulinemia (elevated plasma insulin levels), as they compensatefor the reduced effectiveness of insulin by secreting increased amountsof insulin. This lack of responsiveness to insulin results ininsufficient insulin-mediated activation of uptake, oxidation andstorage of glucose in muscle, and inadequate insulin-mediated repressionof lipolysis in adipose tissue and of glucose production and secretionin the liver.

Persistent or uncontrolled hyperglycemia is associated with increasedand premature morbidity and mortality. Abnormal glucose homeostasis isassociated both directly and indirectly with obesity, hypertension, andalterations of the lipid, lipoprotein and apolipoprotein metabolism, aswell as other metabolic and hemodynamic disease. Patients with Type 2diabetes mellitus have a significantly increased risk of macrovascularand microvascular complications, including atherosclerosis, coronaryheart disease, stroke, peripheral vascular disease, hypertension,nephropathy, neuropathy, and retinopathy. Therefore, therapeutic controlof glucose homeostasis, lipid metabolism, obesity, and hypertension arecritically important in the clinical management and treatment ofdiabetes mellitus.

Patients who have insulin resistance often have Metabolic Syndrome (asdefined in the Third Report of the National Cholesterol EducationProgram Expert Panel on Detection, Evaluation and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel III, or ATP III),National Institutes of Health, 2001, NIH Publication No. 01-3670).Patients with Metabolic Syndrome have an increased risk of developingthe macrovascular and microvascular complications that occur with Type 2diabetes, such as atherosclerosis and coronary heart disease.

There are several available treatments for Type 2 diabetes. Physicalexercise and a reduction in dietary intake of calories are therecommended first-line treatment of Type 2 diabetes and of pre-diabeticconditions associated with insulin resistance, however compliance isgenerally poor. Pharmacologic treatments for diabetes have largelyfocused on three areas of pathophysiology: (1) hepatic glucoseproduction (biguanides, such as phenformin and metformin), (2) insulinresistance (PPAR agonists, such as rosiglitazone, troglitazone,engliazone, balaglitazone, and pioglitazone), (3) insulin secretion(sulfonylureas, such as tolbutamide, glipizide and glimipiride); (4)incretin hormone mimetics (GLP-1 derivatives and analogs, such asexenatide, liraglutide, dulaglutide, semaglutide, lixisenatide,albiglutide and taspoglutide); and (5) inhibitors of incretin hormonedegradation (DPP-4 inhibitors, such as sitagliptin, alogliptin,vildagliptin, linagliptin, denagliptin and saxagliptin).

The two best known biguanides, phenformin and metformin, cause somecorrection of hyperglycemia, but can also induce lactic acidosis andnausea/diarrhea. PPAR gamma agonists, such as rosiglitazone andpioglitazone, are modestly effective in reducing plasma glucose andHemoglobin A1C. However, the currently marketed glitazones do notgreatly improve lipid metabolism and may negatively effect on the lipidprofile. The administration of insulin secretagogues, such as thesulfonylureas (e.g. tolbutamide, glipizide, and glimepiride) can resultin hypoglycemia; their administration must therefore be carefullycontrolled.

There has been a renewed focus on pancreatic islet-based insulinsecretion that is controlled by glucose-dependent insulin secretion.This approach has the potential for stabilization and restoration ofβ-cell function. Several orphan G-protein coupled receptors (GPCR's)have been identified that are preferentially expressed in the β-cell andthat are implicated in glucose stimulated insulin secretion (GSIS).GPR40 is a cell-surface GPCR that is highly expressed in human (androdent) islets as well as in insulin-secreting cell lines. Severalnaturally-occurring medium to long-chain fatty acids (FA's) as well assynthetic compounds, including several members of the thiazolidinedioneclass of PPARγ agonists, have recently been identified as ligands forGPR40 [Itoh, Y. et al., Nature, 422: 173 (2003); Briscoe, C. P. et al.,J. Biol. Chem., 278: 11303 (2003); Kotarsky, K. et al., Biochem.Biophys. Res. Comm., 301: 406 (2003)]. Under hyperglycemic conditions,GPR40 agonists are capable of augmenting the release of insulin fromislet cells. The specificity of this response is suggested by resultsshowing that the inhibition of GPR40 activity by siRNA attenuatesFA-induced amplification of GSIS. These findings indicate that, inaddition to the intracellular generation of lipid-derivatives of FA'sthat are thought to promote insulin release, FA's (and other syntheticGPR40 agonists) may also act as extracellular ligands that bind to GPR40in mediating FA-induced insulin secretion. There are several potentialadvantages of GPR40 as a target for the treatment of Type 2 diabetes.First, since GPR40-mediated insulin secretion is glucose dependent,there is little or no risk of hypoglycemia. Second, the limited tissuedistribution of GPR40 (mainly in islets) suggests that there would beless chance for side effects associated with GPR40 activity in othertissues. Third, GPR40 agonists that are active in the islets may havethe potential to restore or preserve islet function. This would beadvantageous, because long term diabetes therapy often leads to thegradual diminution of islet activity; after extended periods oftreatment, it is often necessary to treat Type 2 diabetic patients withdaily insulin injections. By restoring or preserving islet function,GPR40 agonists may delay or prevent the diminution and loss of isletfunction in a Type 2 diabetic patient.

Compounds that are agonists of G-protein-coupled receptor 40 (GPR40) maybe useful to treat type 2 diabetes mellitus, obesity, hypertension,dyslipidemia, cancer, and metabolic syndrome, as well as cardiovasculardiseases, such as myocardial infarction and stroke, by improving glucoseand lipid metabolism and by reducing body weight. There is a need forpotent GPR40 agonists that have pharmacokinetic and pharmacodynamicproperties suitable for use as human pharmaceuticals.

G-protein-coupled receptor 40 (GPR40) agonists are disclosed in WO2007/136572, WO 2007/136573, WO 2009/058237, WO 2006/083612, WO2006/083781, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO2010/091176, WO 2004/041266, EP 2004/1630152, WO 2004/022551, WO2005/051890, WO 2005/051373, EP 2004/1698624, WO 2005/086661, WO2007/213364, WO 2005/063729, WO 2005/087710, WO 2006/127503, WO2007/1013689, WO 2006/038738, WO 2007/033002, WO 2007/106469, WO2007/123225, WO 2008/001931, WO 2008/030520, WO 2008/030618, WO2008/054674, WO 2008/054675, WO 2008/066097, WO 2008/130514, WO2009/048527, WO 2009/058237, WO 2009/111056, WO 2010/004347, WO2010/045258, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO2010/091176, WO 2010/143733, WO 2012/0004187, WO 2012/011125, WO2012/072691, WO2013/104257, WO 2013/122028, WO 2013/122029, WO2013/128378, WO 2013/178575, WO 2014/073904, WO 2014/078608, WO2014/078609, WO 2014/078610, WO 2014/078611, U.S. Pat. No. 8,030,354,U.S. Pat. No. 8,450,522, CN 103030646, CN 103012343, and GB 2498976.

GPR40 agonists are also disclosed in Negoro et al., ACS MedicinalChemistry Letters (2010), 1(6), 290-294; Walsh et al., Bioorganic &Medicinal Chemistry Letters (2011), 21(11), 3390-3394; Zhou et al.,Bioorganic & Medicinal Chemistry Letters (2010), 20(3), 1298-1301; Houzeet al., Bioorganic & Medicinal Chemistry Letters (2012), 22(2),1267-1270; Lu et al., Bioorganic & Medicinal Chemistry Letters (2013),23(10), 2920-2924; Takano et al., Bioorganic & Medicinal ChemistryLetters (2014), 24(13), 2949-2953; Tan et al., Diabetes (2008), 57(8),2211-2219; Brown et al., ACS Medicinal Chemistry Letters (2012), 3(9),726-730; Lin et al., PloS One (2011), 6(11), e27270; Lou et al., PloSOne (2012), 7(10), e46300; Lin et al., Molecular Pharmacology (2012),82(5), 843-859; Yang, Lihu, Abstracts of Papers, 239th ACS Meeting, SanFrancisco, Calif., USA Mar. 21-25, 2010 MEDI-313; Houze et al.,Abstracts of Papers, 243rd ACS National Meeting & Exposition, San Diego,Calif., USA Mar. 25-29, 2012, MEDI-265; Wang et al., ACS MedicinalChemistry Letters (2013), 4(6), 551-555; and Du et al., ACS MedicinalChemistry Letters (2014), 5(4), 384-389.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted compounds ofstructural formula I:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are agonists ofG-protein-coupled receptor 40 (GPR40) and may be useful in thetreatment, prevention and suppression of diseases, disorders andconditions mediated by agonism of the G-protein-coupled receptor 40,such as Type 2 diabetes mellitus, insulin resistance, hyperglycemia,dyslipidemia, lipid disorders, obesity, hypertension, Metabolic Syndromeand atherosclerosis.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier. The present invention also relates to methods forthe treatment, control or prevention of disorders, diseases, andconditions that may be responsive to agonism of the G-protein-coupledreceptor 40 in a subject in need thereof by administering the compoundsand pharmaceutical compositions of the present invention. The presentinvention also relates to the use of compounds of the present inventionfor manufacture of a medicament useful in treating diseases, disordersand conditions that may be responsive to the agonism of theG-protein-coupled receptor 40. The present invention is also concernedwith treatment of these diseases, disorders and conditions byadministering the compounds of the present invention in combination witha therapeutically effective amount of another agent that may be usefulto treat the disease, disorder and condition. The invention is furtherconcerned with processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof; wherein“a” is a single bond or a double bond, provided that if “a” is a doublebond, then R⁵ and R⁶ are absent and Q is selected from the groupconsisting of: C—R⁴, —C—OC₁₋₆alkyl, and N, and further provided that if“a” is a single bond, then R⁵ and R⁶ are present and Q is selected fromthe group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR⁴R⁶,

(4) S(O)₂,

(5) C═O,

(6) —C(R⁹)OC₁₋₆alkyl, and

(7) —NR^(c);

T is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide;

U is selected from the group consisting of:

(1) CR¹,

(2) N, and

(3) N-oxide;

V is selected from the group consisting of:

(1) CR²,

(2) N, and

(3) N-oxide;

W is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide,

provided that no more than two of T, U, V and W are selected from N andN-oxide, further provided that if both T and W are N or N-oxide, then R³is absent, and further provided that both U and V are not N or N-oxide;

X is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR⁹R⁹,

(4) S(O)₂,

(5) C═O,

(6) —C(R⁹)OC₁₋₆alkyl, and

(7) —NR^(c),

provided that if Q is oxygen, sulfur or —NR^(c), then X is not oxygen,sulfur or —NR^(c), further provided that if Q is C═O, then X is not C═Oor S(O)₂, and further provided that if Q is S(O)₂, then X is not S(O)₂,C═O, oxygen or sulfur;

Y is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR⁹R⁹,

(4) S(O)₂,

(5) C═O,

(6) —C(R⁹)OC₁₋₆alkyl, and

(7) —NR^(c),

provided that if X is oxygen, sulfur or —NR^(c), then Y is not oxygen,sulfur or —NR^(c), further provided that if X is C═O, then Y is not C═Oor S(O)₂, and further provided that if X is S(O)₂, then Y is not S(O)₂,C═O, oxygen or sulfur;

Z is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR⁹R⁹,

(4) S(O)₂,

(5) C═O,

(6) —C(R⁹)OC₁₋₆alkyl, and

(7) —NR^(c);

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) C₃₋₆cycloalkyl, and

(4) C₂₋₅cycloheteroalkyl,

wherein A is unsubstituted or substituted with one to five substituentsselected from R^(a);

B is selected from the group consisting of:

(1) hydrogen,

(2) aryl,

(3) aryl-O—,

(4) aryl-C₁₋₁₀ alkyl-,

(5) aryl-C₁₋₁₀ alkyl-O—,

(6) C₃₋₆cycloalkyl,

(7) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-,

(8) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—,

(9) C₃₋₆cycloalkenyl,

(10) C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-,

(11) C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-O—,

(12) C₂₋₅cycloheteroalkyl,

(13) C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-,

(14) C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-O—,

(15) heteroaryl,

(16) heteroaryl-O—,

(17) heteroaryl-C₁₋₁₀ alkyl-, and

(18) heteroaryl-C₁₋₁₀ alkyl-O—,

wherein B is unsubstituted or substituted with one to five substituentsselected from R^(b);

R¹ and R² are each independently selected from:

(1) a bond,

(2) hydrogen,

(3) halogen,

(4) —OR^(k),

(5) —CN,

(6) —C₁₋₆alkyl,

(7) —C₃₋₆cycloalkyl,

(8) C₃₋₆cycloalkyl-C₁₋₃alkyl-,

(9) —C₂₋₆cycloheteroalkyl, and

(10) C₂₋₆cycloheteroalkyl-C₁₋₃ alkyl-,

wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷,

or R¹ and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷;R³ is absent or selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —OR^(e),

(4) —CN,

(5) —C₁₋₆alkyl,

(6) —C₃₋₆cycloalkyl, and

(7) C₃₋₆cycloalkyl-C₁₋₃alkyl-,

wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(i);

R⁴ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) OR^(e),

(4) C₀₋₅alkylNR^(c)R^(d),

(5) C₁₋₆alkyl,

(6) C₁₋₆alkyl-O—,

(7) C₃₋₆cycloalkyl,

(8) C₃₋₆cycloalkyl-O—,

(9) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-,

(10) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—,

(11) C₂₋₅cycloheteroalkyl,

(12) C₂₋₅cycloheteroalkyl-O—,

(13) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-,

(14) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-O—,

(15) aryl,

(16) aryl-O—,

(17) aryl-C₁₋₁₀alkyl-,

(18) heteroaryl,

(19) heteroaryl-O—, and

(20) heteroaryl-C₁₋₁₀alkyl-,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituents selectedfrom R^(j),

provided that when R⁴ is selected from the group consisting of:

-   -   (1) OR^(e),    -   (2) C₀alkyl-NR^(c)R^(d),    -   (3) C₁₋₆alkyl-O—,    -   (4) C₃₋₆cycloalkyl-O—,    -   (5) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—,    -   (6) C₂₋₅cycloheteroalkyl-O—,    -   (7) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-O—,    -   (8) aryl-O—, and    -   (9) heteroaryl-O—,        then X is selected from the group consisting of:    -   (1) —CR⁹R⁹,    -   (2) C═O, and    -   (3) —C(R⁹)OC₁₋₆alkyl;        R⁵ is absent or selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) —C₃₋₆cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(j);

R⁶ is absent or selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) —C₃₋₆cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(j);

R⁷ is selected from the group consisting of:

(1) —CO₂R⁸,

(2) —C₁₋₆alkyl-CO₂R⁸,

(3) —C₁₋₆alkyl-CONHSO₂R^(m),

(4) —C₁₋₆alkyl-SO₂NHCOR^(m),

(5) —C₁₋₆alkyl-tetrazolyl, and

(6) a cycloheteroalkyl selected from the group consisting of:

R⁸ is selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —C₃₋₆cycloalkyl, and

(4) aryl-C₁₋₆alkyl,

wherein each alkyl, cycloalkyl and aryl is unsubstituted or substitutedwith one to three substituents selected from R^(j);

R⁹ is selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) halogen,

(4) —(CH₂)₀₋₅OH,

(5) —(CH₂)₀₋₅OC₁₋₆alkyl,

(6) —(CH₂)₀₋₅NR^(c)R^(d),

(7) —C₃₋₆cycloalkyl, and

(8) aryl-C₁₋₆alkyl,

wherein CH₂ is unsubstituted or substituted with one or two substituentsselected from R^(j), and wherein alkyl, cycloalkyl and aryl isunsubstituted or substituted with one to three substituents selectedfrom R^(j);

R^(a) is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) halogen,

(3) —C₀₋₆alkyl-OR^(e),

(4) —C₀₋₆alkyl-NR^(c)S(O)_(n)R^(e),

(5) —C₀₋₆alkyl-S(O)_(n)R^(e),

(6) —C₀₋₆alkyl-S(O)_(n)NR^(c)R^(d),

(7) —C₀₋₆alkyl-NR^(c)R^(d),

(8) —C₀₋₆alkyl-C(O)R^(e),

(9) —C₀₋₆alkyl-OC(O)R^(e),

(10) —C₀₋₆alkyl-CO₂R^(e),

(11) —C₀₋₆alkyl-CN,

(12) —C₀₋₆alkyl-C(O)NR^(c)R^(d),

(13) —C₀₋₆alkyl-NR^(c)C(O)R^(e),

(14) —C₀₋₆alkyl-NR^(c)C(O)OR^(e),

(15) —C₀₋₆alkyl-NR^(c)C(O)NR^(c)R^(d),

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) —C₀₋₆alkyl-aryl,

(20) —C₀₋₆alkyl-heteroaryl,

(21) —C₀₋₆alkyl-C₃₋₁₀cycloalkyl,

(22) —C₀₋₆alkyl-C₃₋₁₀cycloalkenyl, and

(23) —C₀₋₆alkyl-C₂₋₁₀cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to five substituentsindependently selected from: —C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl,—S(O)₂—C₁₋₄alkyl, —CN, —OCHF₂, —OCF₃, —CF₃, and —C₀₋₆alkyl-NR^(c)R^(d);R^(b) is selected from the group consisting of:

(1) —C₁₋₁₀alkyl,

(2) —C₂₋₁₀alkenyl,

(3) —CF₃,

(4) halogen,

(5) —CN,

(6) —OH,

(7) —OC₁₋₁₀alkyl,

(8) —OC₂₋₁₀alkenyl,

(9) —O(CH₂)pOC₁₋₁₀alkyl,

(10) —O(CH₂)pC₃₋₆cycloalkyl,

(11) —O(CH₂)pC₃₋₆ cycloalkyl-C₁₋₁₀alkyl,

(12) —O(CH₂)pC₂₋₅cycloheteroalkyl,

(13) —O(CH₂)pC₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl,

(14) —O-aryl,

(15) —O-heteroaryl,

(16) —O-aryl-C₁₋₁₀alkyl,

(17) —O-heteroaryl-C₁₋₁₀alkyl,

(18) —O(CH₂)pNR^(c)S(O)_(m)R^(e),

(19) —O(CH₂)pS(O)_(m)R^(e),

(20) —O(CH₂)pS(O)_(m)NR^(c)R^(d),

(21) —O(CH₂)pNR^(c)R^(d),

(22) —C(O)R^(e),

(23) —OC(O)R^(e),

(24) —CO₂R^(e),

(25) —C(O)NR^(c)R^(d),

(26) —NR^(c)C(O)R^(e),

(27) —NR^(c)C(O)OR^(e),

(28) —NR^(c)C(O)NR^(c)R^(d),

(29) —O(CH₂)pO—C₃₋₆cycloalkyl,

(30) —O(CH₂)pO—C₂₋₅ cycloheteroalkyl,

(31) —OCF₃,

(32) —OCHF₂,

(33) —(CH₂)pC₃₋₆cycloalkyl,

(34) —(CH₂)pC₂₋₅ cycloheteroalkyl,

(35) aryl,

(36) heteroaryl,

(37) aryl-C₁₋₁₀alkyl-, and

(38) heteroaryl-C₁₋₁₀alkyl-,

wherein each CH, CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with one to fivesubstituents independently selected from: —C₁₋₆alkyl, halogen, OH,—O—C₁₋₆alkyl and —CF₃;

R^(c) and R^(d) are each independently selected from the groupconsisting of:

(1) hydrogen,

(2) C₁₋₁₀alkyl,

(3) C₂₋₁₀alkenyl,

(4) C₃₋₆cycloalkyl,

(5) C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-,

(6) C₂₋₅cycloheteroalkyl,

(7) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-,

(8) aryl,

(9) heteroaryl,

(10) aryl-C₁₋₁₀alkyl-, and

(11) heteroaryl-C₁₋₁₀alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from R^(f),

or R^(c) and R^(d) together with the atom(s) to which they are attachedform a C₂₋₁₀ cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein eachR^(c) and R^(d) is unsubstituted or substituted with one to threesubstituents independently selected from R^(f);each R^(e) is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₁₀alkyl,

(3) —C₂₋₁₀ alkenyl,

(4) —C₃₋₆ cycloalkyl,

(5) C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-,

(6) —C₂₋₅cycloheteroalkyl,

(7) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-,

(8) aryl,

(9) aryl-C₁₋₁₀alkyl-,

(10) heteroaryl, and

(11) heteroaryl-C₁₋₁₀alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to threesubstituents selected from R^(h);

each R^(f) is selected from the group consisting of:

(1) halogen,

(2) C₁₋₁₀alkyl,

(3) —OH,

(4) —O—C₁₋₄alkyl,

(5) —S(O)_(m)—C₁₋₄alkyl,

(6) —CN,

(7) —CF₃,

(8) —OCHF₂, and

(9) —OCF₃,

wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, C₁₋₆alkyl, cyanoand S(O)₂C₁₋₆alkyl;

each R^(g) is independently selected from the group consisting of:

(1) hydrogen,

(2) —C(O)R^(e), and

(3) —C₁₋₁₀alkyl,

wherein alkyl is unsubstituted or substituted with one to five halogens;

each R^(h) is independently selected from the group consisting of:

(1) halogen,

(2) C₁₋₁₀alkyl,

(3) —OH,

(4) —O—C₁₋₄alkyl,

(5) —S(O)_(m)—C₁₋₄alkyl,

(6) —CN,

(7) —CF₃,

(8) —OCHF₂, and

(9) —OCF₃,

wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, C₁₋₆alkyl, cyanoand S(O)₂C₁₋₆alkyl;

each R^(i) is independently selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —OR^(e),

(3) —NR^(c)S(O)_(m)R^(e),

(4) halogen,

(5) —S(O)_(m)R^(e),

(6) —S(O)_(m)NR^(c)R^(d),

(7) —NR^(c)R^(d),

(8) —C(O)R^(e),

(9) —OC(O)R^(e),

(10) —CO₂R^(e),

(11) —CN,

(12) —C(O)NR^(c)R^(d),

(13) —NR^(c)C(O)R^(e),

(14) —NR^(c)C(O)OR^(e),

(15) —NR^(c)C(O)NR^(c)R^(d),

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) —C₃₋₆cycloalkyl, and

(20) —C₂₋₅cycloheteroalkyl;

each R^(j) is independently selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —OR^(e),

(3) —NR^(c)S(O)_(m)R^(e),

(4) halogen,

(5) —S(O)_(m)R^(e),

(6) —S(O)_(m)NR^(c)R^(d),

(7) —NR^(c)R^(d),

(8) —C(O)R^(e),

(9) —OC(O)R^(e),

(10) —CO₂R^(e),

(11) —CN,

(12) —C(O)NR^(c)R^(d),

(13) —NR^(c)C(O)R^(e),

(14) —NR^(c)C(O)OR^(e),

(15) —NR^(c)C(O)NR^(c)R^(d),

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) —C₃₋₆cycloalkyl, and

(20) —C₂₋₅cycloheteroalkyl;

each R^(k) is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆ alkyl,

(3) —C₁₋₆alkyl-SO₂C₁₋₆alkyl,

(4) —CF₃, and

(5) —CHF₂,

wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, —OC₁₋₆alkyl, halogen,cyano, and —S(O)₂C₁₋₆alkyl;

each R^(L) is independently selected from the group consisting of:

(1) —CO₂C₁₋₆alkyl,

(2) —C₁₋₁₀alkyl,

(3) —C₂₋₁₀ alkenyl,

(4) —C₂₋₁₀alkynyl,

(5) —C₃₋₆cycloalkyl,

(6) —C₂₋₆cycloheteroalkyl,

(7) aryl, and

(8) heteroaryl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with one to foursubstituents independently selected from C₁₋₆alkyl, halogen, and—OC₁₋₆alkyl;

each R^(m) is independently selected from the group consisting of:

(1) —C₁₋₁₀alkyl,

(2) —C₂₋₁₀ alkenyl,

(3) —C₃₋₆ cycloalkyl,

(4) C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-,

(5) —C₂₋₅cycloheteroalkyl,

(6) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-,

(7) aryl,

(8) heteroaryl,

(9) aryl-C₁₋₁₀alkyl-, and

(10) heteroaryl-C₁₋₁₀alkyl-;

-   each n is independently selected from: 0, 1 or 2;-   each m is independently selected from: 0, 1 or 2;-   each p is independently selected from: 0, 1, 2, 3, 4, 5 or 6; and-   each r is independently selected from: 0, 1, 2 or 3.

The invention has numerous embodiments, which are summarized below. Theinvention includes the compounds as shown, and also includes individualdiastereoisomers, enantiomers, and epimers of the compounds, andmixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment of the present invention, “a” is a single bond. Inanother embodiment of the present invention, “a” is a single bond; andR⁵ and R⁶ are present.

In another embodiment of the present invention, “a” is a double bond andR⁵ and R⁶ are absent. In another embodiment, “a” is a double bond, R⁵and R⁶ are absent and Q is selected from the group consisting of: C—R⁴,—C—OC₁₋₆alkyl, and N.

In another embodiment of the present invention, “a” is a single bond,and Q is selected from the group consisting of: oxygen, sulfur, —CR⁴R⁶,S(O)₂, C═O, —C(R⁹)OC₁₋₆alkyl, and —NR^(c). In another embodiment of thepresent invention, “a” is a single bond, R⁵ and R⁶ are present, and Q isselected from the group consisting of: oxygen, sulfur, —CR⁴R⁶, S(O)₂,C═O, —C(R⁹)OC₁₋₆alkyl, and —NR^(c).

In another embodiment of the present invention, T is selected from thegroup consisting of: CH, N and N-oxide. In a class of this embodiment, Tis selected from the group consisting of: CH and N. In another class ofthis embodiment, T is CH. In another class of this embodiment, T is N orN-oxide. In another class of this embodiment, T is N. In another classof this embodiment, T is N-oxide.

In another embodiment of the present invention, U is selected from thegroup consisting of: CR¹, N and N-oxide. In a class of this embodiment,U is selected from the group consisting of: CR¹ and N. In another classof this embodiment, U is CR¹. In another class of this embodiment, U isN or N-oxide. In another class of this embodiment, U is N. In anotherclass of this embodiment, U is N-oxide.

In another embodiment of the present invention, V is selected from thegroup consisting of: CR², N and N-oxide. In a class of this embodiment,V is selected from the group consisting of: CR² and N. In another classof this embodiment, V is CR². In another class of this embodiment, V isN or N-oxide. In another class of this embodiment, V is N. In anotherclass of this embodiment, V is N-oxide.

In another embodiment of the present invention, W is selected from thegroup consisting of: CH, N and N-oxide, provided that no more than twoof T, U, V and W are selected from N and N-oxide, further provided thatif both T and W are N or N-oxide, then R³ is absent, and furtherprovided that both U and V are not N or N-oxide. In a class of thisembodiment, W is selected from the group consisting of: CH and N,provided that no more than two of T, U, V and W are selected from N andN-oxide, further provided that if both T and W are N or N-oxide, then R³is absent, and further provided that both U and V are not N or N-oxide.In another class of this embodiment, W is CH, provided that no more thantwo of T, U, V and W are selected from N and N-oxide, further providedthat if both T and W are N or N-oxide, then R³ is absent, and furtherprovided that both U and V are not N or N-oxide. In another class ofthis embodiment, W is N or N-oxide, provided that no more than two of T,U, V and W are selected from N and N-oxide, further provided that ifboth T and W are N or N-oxide, then R³ is absent, and further providedthat both U and V are not N or N-oxide. In another class of thisembodiment, W is N, provided that no more than two of T, U, V and W areselected from N and N-oxide, further provided that if both T and W are Nor N-oxide, then R³ is absent, and further provided that both U and Vare not N or N-oxide.

In another embodiment of the present invention, W is selected from thegroup consisting of: CH, N and N-oxide. In a class of this embodiment, Wis selected from the group consisting of: CH and N. In another class ofthis embodiment, W is CH. In another class of this embodiment, W is N orN-oxide. In another class of this embodiment, W is N. In another classof this embodiment, W is N-oxide.

In another embodiment of the present invention, T is CH, U is CR¹, V isCR², and W is CH. In a class of this embodiment, T is CH, U is CR¹, V isCH, and W is CH. In another class of this embodiment, T is CH, U is CH,V is CR², and W is CH.

In another embodiment of the present invention, T is N or N-oxide, U isCR¹, V is CR², and W is CH. In a class of this embodiment, T is N, U isCR¹, V is CR², and W is CH. In another embodiment of the presentinvention, T is CH, U is N or N-oxide, and V is CR², and W is CH. In aclass of this embodiment, T is CH, U is N, V is CR², and W is CH. Inanother embodiment of the present invention, T is CH, U is CR¹, V is Nor N-oxide, and W is CH. In a class of this embodiment, T is CH, U isCR¹, and V is N or N-oxide, and W is CH. In another embodiment of thepresent invention, T is CH, U is CR¹, V is CR², and W is CH, N orN-oxide. In another embodiment of the present invention, T is CH, U isCR¹, V is CR², and W is N or N-oxide. In a class of this embodiment, Tis CH, U is CR¹, V is CR², and W is N.

In another embodiment of the present invention, T is N or N-oxide, U isN or N-oxide, V is CR², and W is CH. In a class of this embodiment, T isN, U is N, V is CR², and W is CH. In another embodiment of the presentinvention, T is N or N-oxide, U is CR¹, V is N or N-oxide, and W is CH.In a class of this embodiment, T is N, U is CR¹, V is N, and W is CH. Inanother embodiment of the present invention, T is N or N-oxide, U isCR¹, V is CR², and W is N or N-oxide. In a class of this embodiment, Tis N, U is CR¹, V is CR², and W is N.

In another embodiment of the present invention, T is N or N-oxide, U isCR¹, V is CR², and W is N or N-oxide; and R³ is absent. In a class ofthis embodiment, T is N, U is CR¹, V is CR², and W is N; and R³ isabsent. In another embodiment of the present invention, T is CH, U is Nor N-oxide, V is CR², and W is N or N-oxide. In a class of thisembodiment, T is CH, U is N, V is CR², and W is N. In another embodimentof the present invention, T is CH, U is CR¹, V is N or N-oxide, and W isN or N-oxide. In a class of this embodiment, T is CH, U is CR¹, V is N,and W is N. In another embodiment of the present invention, T is CH; Uis CR¹; V is CR²; and W is CH, N or N-oxide.

In another embodiment of the present invention, Q is selected from thegroup consisting of: oxygen, sulfur, —CR⁴R⁶, C═O, —C(R⁹)OC₁₋₆alkyl, and—NR^(c). In another embodiment of the present invention, Q is selectedfrom the group consisting of: oxygen, sulfur, —CR⁴R⁶, —C(R⁹)OC₁₋₆alkyl,and —NR^(c). In another embodiment of the present invention, Q isselected from the group consisting of: oxygen, sulfur, —CR⁴R⁶, and—NR^(c). In another embodiment of the present invention, Q is selectedfrom the group consisting of: oxygen, —CR⁴R⁶, and —NR^(c). In anotherembodiment of the present invention, Q is selected from the groupconsisting of: oxygen, and —CR⁴R⁶. In a class of this embodiment, Q isselected from the group consisting of: oxygen, and —CH₂.

In another embodiment of the present invention, Q is oxygen. In anotherembodiment of the present invention, Q is —CR⁴R⁶. In a class of thisembodiment, Q is —CH₂. In another class of this embodiment, Q is —CH.

In another embodiment of the present invention, X is selected from thegroup consisting of: oxygen, —CR⁹R⁹, S(O)₂, C═O, —C(R⁹)OC₁₋₆alkyl, and—NR^(c), provided that if Q is oxygen, sulfur or —NR^(c), then X is notoxygen or —NR^(c), further provided that if Q is C═O, then X is not C═Oor S(O)₂, and further provided that if Q is S(O)₂, then X is not S(O)₂,C═O, or oxygen. In another embodiment of the present invention, X isselected from the group consisting of: oxygen, —CR⁹R⁹, S(O)₂, C═O, and—NR^(c), provided that if Q is oxygen, sulfur or —NR^(c), then X is notoxygen or —NR^(c), further provided that if Q is C═O, then X is not C═Oor S(O)₂, and further provided that if Q is S(O)₂, then X is not S(O)₂,C═O, or oxygen.

In another embodiment of the present invention, X is selected from thegroup consisting of: oxygen, —CR⁹R⁹, C═O, and —NR^(c), provided that ifQ is oxygen, sulfur or —NR^(c), then X is not oxygen or —NR^(c), furtherprovided that if Q is C═O, then X is not C═O, and further provided thatif Q is S(O)₂, then X is not C═O, or oxygen. In another embodiment ofthe present invention, X is selected from the group consisting of:oxygen, —CR⁹R⁹, and —NR^(c), provided that if Q is oxygen, sulfur or—NR^(c), then X is not oxygen or —NR^(c), and further provided that if Qis S(O)₂, then X is not oxygen. In another embodiment of the presentinvention, X is oxygen. In another embodiment of the present invention,X is —NR^(c). In another embodiment of the present invention, X is—CR⁹R⁹. In a class of this embodiment, X is —CH₂.

In another embodiment of the present invention, X is selected from thegroup consisting of: —CR⁹, —C—OC₁₋₆alkyl, and —N, provided that if Q isoxygen, sulfur or —NR^(c), then X is not —N. In another embodiment ofthe present invention, X is selected from the group consisting of: —CR⁹,and —N, provided that if Q is oxygen, sulfur or —NR^(c), then X is not—N. In another embodiment of the present invention, X is —N. In anotherembodiment of the present invention, X is —CR⁹. In a class of thisembodiment, X is —CH—.

In another embodiment of the present invention, Y is selected from thegroup consisting of: oxygen, —CR⁹R⁹, S(O)₂, C═O, —C(R⁹)OC₁₋₆alkyl, and—NR^(c), that if X is oxygen, sulfur or —NR^(c), then Y is not oxygen or—NR^(c), further provided that if X is C═O, then Y is not C═O or S(O)₂,and further provided that if X is S(O)₂, then Y is not S(O)₂, C═O, oroxygen. In another embodiment of the present invention, Y is selectedfrom the group consisting of: oxygen, —CR⁹R⁹, S(O)₂, C═O, and —NR^(c),provided that if X is oxygen, sulfur or —NR^(c), then Y is not oxygen,or —NR^(c), further provided that if X is C═O, then Y is not C═O orS(O)₂, and further provided that if X is S(O)₂, then Y is not S(O)₂,C═O, or oxygen. In another embodiment of the present invention, Y isselected from the group consisting of: oxygen, —CR⁹R⁹, C═O, and —NR^(c),provided that if X is oxygen, sulfur or —NR^(c), then Y is not oxygen,or —NR^(c), further provided that if X is C═O, then Y is not C═O, andfurther provided that if X is S(O)₂, then Y is not C═O, or oxygen.

In another embodiment of the present invention, Y is selected from thegroup consisting of: oxygen, —CR⁹R⁹, and —NR^(c), provided that if X isoxygen, sulfur or —NR^(c), then Y is not oxygen, or —NR^(c), and furtherprovided that if X is S(O)₂, then Y is not oxygen. In another embodimentof the present invention, Y is oxygen. In another embodiment of thepresent invention, Y is —NR^(c). In another embodiment of the presentinvention, Y is —CR⁹R⁹. In a class of this embodiment, Y is —CH₂.

In another embodiment of the present invention, Y is selected from thegroup consisting of: —CR⁹, —C—OC₁₋₆alkyl, and —N, provided that if X isoxygen, sulfur or —NR^(c), then Y is not —N. In another embodiment ofthe present invention, Y is selected from the group consisting of: —CR⁹,and —N, provided that if X is oxygen, sulfur or —NR^(c), then Y is not—N. In another embodiment of the present invention, Y is —N. In anotherembodiment of the present invention, Y is —CR⁹R⁹. In a class of thisembodiment, Y is —CH₂.

In another embodiment of the present invention, Z is selected from thegroup consisting of: oxygen, —CR⁹R⁹, S(O)₂, and —NR^(c). In anotherembodiment of the present invention, Z is selected from the groupconsisting of: oxygen, —CR⁹R⁹, and —NR^(c). In another embodiment of thepresent invention, Z is selected from the group consisting of: oxygen,and —CR⁹R⁹. In another embodiment of the present invention, Z isselected from the group consisting of: oxygen, and —NR^(c). In anotherembodiment of the present invention, Z is —NR^(c). In another embodimentof the present invention, Z is S(O)₂. In another embodiment of thepresent invention, Z is —CR⁹R⁹. In a class of this embodiment, Z is CH₂.In another embodiment of the present invention, Z is oxygen.

In another embodiment of the present invention, A is selected from thegroup consisting of: aryl, heteroaryl, and C₂₋₅cycloheteroalkyl, whereineach aryl, heteroaryl and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(a). In aclass of this embodiment, A is selected from the group consisting of:phenyl, pyridyl, and azetidine, wherein each phenyl, pyridyl andazetidine is unsubstituted or substituted with one to four substituentsselected from R^(a). In another class of this embodiment, A is selectedfrom the group consisting of: phenyl, pyridyl, azetidine and pyrazinyl,wherein each phenyl, pyridyl, azetidine and pyrazinyl is unsubstitutedor substituted with one to four substituents selected from R^(a). Inanother embodiment of the present invention, A is selected from thegroup consisting of: aryl, and heteroaryl, wherein each aryl andheteroaryl is unsubstituted or substituted with one to five substituentsselected from R^(a). In a class of this embodiment, A is selected fromthe group consisting of: phenyl, pyridyl and pyrazinyl, wherein phenyl,pyridyl and pyrazinyl is unsubstituted or substituted with one to foursubstituents selected from R^(a). In another class of this embodiment, Ais selected from the group consisting of: phenyl and pyridyl, whereineach phenyl and pyridyl is unsubstituted or substituted with one to foursubstituents selected from R^(a). In another embodiment of the presentinvention, A is selected from the group consisting of: aryl, whereinaryl is unsubstituted or substituted with one to five substituentsselected from R^(a). In a class of this embodiment, A is phenyl, whereinphenyl is unsubstituted or substituted with one to five substituentsselected from R^(a). In another embodiment of the present invention, Ais selected from the group consisting of: heteroaryl, wherein heteroarylis unsubstituted or substituted with one to five substituents selectedfrom R^(a). In a class of this embodiment, A is selected from the groupconsisting of: pyridyl and pyrazinyl, wherein each pyridyl and pyrazinylis unsubstituted or substituted with one to four substituents selectedfrom R^(a). In another class of this embodiment, A is pyrazinyl, whereinpyrazinyl is unsubstituted or substituted with one to four substituentsselected from R^(a). In another class of this embodiment, A is pyridyl,wherein pyridyl is unsubstituted or substituted with one to foursubstituents selected from R^(a). In another embodiment of the presentinvention, A is selected from the group consisting of:C₂₋₅cycloheteroalkyl, wherein each cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(a). In aclass of this embodiment, A is azetidine, wherein azetidine isunsubstituted or substituted with one to four substituents selected fromR^(a).

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, aryl-O—, aryl-C₁₋₁₀ alkyl-, aryl-C₁₋₁₀alkyl-O—, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₁₀alkyl-,C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—, C₃₋₆cycloalkenyl,C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-, C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-O—,C₂₋₅cycloheteroalkyl, C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-,C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-O—, heteroaryl, heteroaryl-O—,heteroaryl-C₁₋₁₀ alkyl-, and heteroaryl-C₁₋₁₀ alkyl-O—, wherein B isunsubstituted or substituted with one to five substituents selected fromR^(b).

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, aryl-C₁₋₁₀ alkyl-, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₁₀alkyl-, C₃₋₆cycloalkenyl,C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-, C₂₋₅cycloheteroalkyl,C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl, heteroaryl, and heteroaryl-C₁₋₁₀alkyl-, wherein B is unsubstituted or substituted with one to fivesubstituents selected from R^(b). In another embodiment of the presentinvention, B is selected from the group consisting of: aryl, aryl-C₁₋₁₀alkyl-, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₁₀alkyl-,C₂₋₅cycloheteroalkyl, C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl, heteroaryl, andheteroaryl-C₁₋₁₀ alkyl-, wherein B is unsubstituted or substituted withone to five substituents selected from R^(b). In another embodiment ofthe present invention, B is selected from the group consisting of: aryl,aryl-C₁₋₁₀ alkyl-, C₃₋₆cycloalkyl, C₂₋₅cycloheteroalkyl, heteroaryl, andheteroaryl-C₁₋₁₀ alkyl-, wherein B is unsubstituted or substituted withone to five substituents selected from R^(b).

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, aryl-C₁₋₁₀ alkyl-, and heteroaryl, whereineach alkyl, aryl and heteroaryl is unsubstituted or substituted with oneto five substituents selected from R^(b). In a class of this embodiment,B is selected from the group consisting of: phenyl, —CH₂-phenyl, andpyridyl, wherein each phenyl and pyridyl is unsubstituted or substitutedwith one to five substituents selected from R^(b).

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, wherein each aryl is unsubstituted orsubstituted with one to five substituents selected from R^(b). In aclass of this embodiment, B is phenyl, wherein each phenyl isunsubstituted or substituted with one to five substituents selected fromR^(b). In another embodiment of the present invention, B is selectedfrom the group consisting of: aryl-C₁₋₁₀ alkyl-, wherein each alkyl andaryl is unsubstituted or substituted with one to five substituentsselected from R^(b). In a class of this embodiment, B is selected fromthe group consisting of: —CH₂-phenyl, wherein each phenyl isunsubstituted or substituted with one to five substituents selected fromR^(b). In another embodiment of the present invention, B is selectedfrom the group consisting of: heteroaryl, wherein each heteroaryl isunsubstituted or substituted with one to five substituents selected fromR^(b). In a class of this embodiment, B is selected from the groupconsisting of: pyridyl, wherein each pyridyl is unsubstituted orsubstituted with one to five substituents selected from R^(b).

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, halogen, —OR^(k), —CN,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein one ofR¹ and R² is substituted with R⁷, or R¹ and R² together with the atom(s)to which they are attached form a C₃₋₆cycloalkyl ring or aC₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, halogen, —OR^(k), —CN,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein one ofR¹ and R² is substituted with R⁷. In another embodiment of the presentinvention, R¹ and R² are each independently selected from: hydrogen,halogen, —OR^(k), —CN, and —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷, or R¹and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, halogen, —OR^(k), —CN, and—C₁₋₆alkyl, wherein each alkyl is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen and —C₁₋₆alkyl, wherein each alkylis unsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷, or R¹and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, and —C₁₋₆alkyl, wherein eachalkyl is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷. In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, and ethyl, wherein ethyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷, or R¹and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, and ethyl, wherein ethyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷. Inanother class of this embodiment, R¹ is selected from: a bond, hydrogen,halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷.

In another embodiment of the present invention, R¹ is selected from:hydrogen, halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷.

In another embodiment of the present invention, R¹ is—CH(cyclopropyl)-CH(CH₃)—CO₂H. In another embodiment of the presentinvention, R¹ is —CH(cyclopropyl)-CH(CH₃)—CO₂H, and R² is hydrogen. Inanother embodiment of the present invention, R² is—CH(cyclopropyl)-CH(CH₃)—CO₂H. In another embodiment of the presentinvention, R² is —CH(cyclopropyl)-CH(CH₃)—CO₂H, and R¹ is hydrogen.

In another embodiment of the present invention, R¹ is —(CH₂)₂—CO₂H. Inanother embodiment of the present invention, R¹ is —(CH₂)₂—CO₂H, and R²is hydrogen. In another embodiment of the present invention, R² is—(CH₂)₂—CO₂H. In another embodiment of the present invention, R² is—(CH₂)₂—CO₂H, and R¹ is hydrogen.

In another embodiment of the present invention, R¹ is selected from:hydrogen, halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷. In another embodiment of the present invention, R¹is selected from: hydrogen, halogen, —OR^(k), and —CN.

In another embodiment of the present invention, R¹ is selected from:—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R¹ issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷.

In another embodiment of the present invention, R¹ is selected from:—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R¹ issubstituted with R⁷. In another embodiment of the present invention, R¹is selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R¹ is substituted with R⁷;and R² is hydrogen.

In another embodiment of the present invention, R¹ is selected from:hydrogen, halogen, —OR^(k), —CN, and —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷, or R¹and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷. In another embodiment of the present invention,R¹ is selected from: hydrogen, halogen, —OR^(k), —CN, and —C₁₋₆alkyl,wherein each alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷.

In another embodiment of the present invention, R¹ is selected from:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷, or R¹ and R² togetherwith the atom(s) to which they are attached form a C₃₋₆cycloalkyl ringor a C₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷. In another embodiment of the present invention, R¹ is selected from:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷. In another embodimentof the present invention, R¹ is selected from: hydrogen and ethyl,wherein ethyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷. In another embodiment of the present invention, R¹is hydrogen. In another embodiment of the present invention, R¹ isselected from: —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R¹ issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷. In another embodimentof the present invention, R¹ is ethyl, wherein ethyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein R¹ is substituted with R⁷, or R¹ and R² together with theatom(s) to which they are attached form a C₃₋₆cycloalkyl ring or aC₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷.

In another embodiment of the present invention, R¹ is selected from:—C₁₋₆alkyl, wherein each alkyl is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein R¹ is substitutedwith R⁷. In another embodiment of the present invention, R¹ is ethyl,wherein ethyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R¹ is substituted with R⁷.

In another embodiment of the present invention, R¹ is selected from:—C₁₋₆alkyl, wherein each alkyl is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein R¹ is substitutedwith R⁷; and R² is hydrogen. In another embodiment of the presentinvention, R¹ is ethyl, wherein ethyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R¹ issubstituted with R⁷; and R² is hydrogen.

In another embodiment of the present invention, R¹ is hydrogen. Inanother embodiment, R¹ is independently selected from: a bond, halogen,—OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R¹ issubstituted with R⁷; and R² is hydrogen.

In another embodiment, R² is selected from: a bond, hydrogen, halogen,—OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein one ofR¹ and R² is substituted with R⁷, or R¹ and R² together with the atom(s)to which they are attached form a C₃₋₆cycloalkyl ring or aC₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷.

In another embodiment of the present invention, R² is selected from:hydrogen, halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from: hydrogen, and —C₁₋₆alkyl, wherein one of R¹and R² is —C₁₋₆alkyl substituted with R⁷, and wherein alkyl isunsubstituted or substituted with one to three substituentsindependently selected from R^(L); or a pharmaceutically acceptable saltthereof. In another embodiment of the present invention, R¹ and R² areeach independently selected from: hydrogen, and ethyl, wherein one of R¹and R² is ethyl substituted with R⁷, and wherein ethyl is unsubstitutedor substituted with one to three substituents independently selectedfrom R^(L); or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, R² is selected from:hydrogen, halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷. In another embodiment of the present invention, R²is selected from: hydrogen, halogen, —OR^(k), and —CN.

In another embodiment of the present invention, R² is selected from:—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R² issubstituted with R⁷, or R¹ and R² together with the atom(s) to whichthey are attached form a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkylring containing 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R¹ and R² is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with R⁷.

In another embodiment of the present invention, R² is selected from:—C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein R² issubstituted with R⁷. In another embodiment of the present invention, R²is selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R² is substituted with R⁷;and R¹ is hydrogen.

In another embodiment of the present invention, R² is selected from:hydrogen, halogen, —OR^(k), —CN, and —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷, or R¹and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷. In another embodiment of the present invention,R² is selected from: hydrogen, halogen, —OR^(k), —CN, and —C₁₋₆alkyl,wherein each alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with R⁷.

In another embodiment of the present invention, R² is selected from:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein one ofR¹ and R² is substituted with R⁷, or R¹ and R² together with the atom(s)to which they are attached form a C₃₋₆cycloalkyl ring or aC₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷.

In another embodiment of the present invention, R² is selected from:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from R^(L), and wherein one ofR¹ and R² is substituted with R⁷. In another embodiment of the presentinvention, R² is selected from: hydrogen and ethyl, wherein ethyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with R⁷. Inanother embodiment of the present invention, R² is hydrogen. In anotherembodiment of the present invention, R² is ethyl, wherein ethyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein R² is substituted with R⁷, or R¹ and R² togetherwith the atom(s) to which they are attached form a C₃₋₆cycloalkyl ringor a C₂₋₅cycloheteroalkyl ring containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and N—R^(g), wherein each R¹and R² is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein one of R¹ and R² is substituted withR⁷.

In another embodiment of the present invention, R² is selected from:ethyl, wherein ethyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R² is substituted with R⁷,or R¹ and R² together with the atom(s) to which they are attached form aC₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(g), wherein each R¹ and R² is unsubstituted or substituted with oneto three substituents selected from R^(L), and wherein one of R¹ and R²is substituted with R⁷.

In another embodiment of the present invention, R² is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R² is substituted with R⁷.In another embodiment of the present invention, R² is ethyl, whereinethyl is unsubstituted or substituted with one to three substituentsselected from R^(L), and wherein R² is substituted with R⁷.

In another embodiment of the present invention, R² is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R² is substituted with R⁷;and R¹ is hydrogen. In another embodiment of the present invention, R²is ethyl, wherein ethyl is unsubstituted or substituted with one tothree substituents selected from R^(L), and wherein R² is substitutedwith R⁷; and R¹ is hydrogen.

In another embodiment, R² is independently selected from: a bond,halogen, —OR^(k), —CN, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein R² is substituted with R⁷;and R¹ is hydrogen.

In one class of the embodiments of the present invention, at least oneof R¹ and R² is selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃alkyl-, —C₂₋₆cycloheteroalkyl, andC₂₋₆cycloheteroalkyl-C₁₋₃alkyl-. wherein each alkyl, cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from R^(L), and wherein one alkyl,cycloalkyl or cycloheteroalkyl is substituted with R⁷. In another classof the embodiments of the present invention, one of R¹ and R² isselected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₃alkyl-,—C₂₋₆cycloheteroalkyl, and C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents independently selected from R^(L), andwherein one alkyl, cycloalkyl or cycloheteroalkyl is substituted withR⁷. In another class of the embodiments of the present invention, atleast one of R¹ and R² is —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents independently selected fromR^(L), and wherein one alkyl is substituted with R⁷. In another class ofthe embodiments of the present invention, one of R¹ and R² is—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents independently selected from R^(L), and wherein alkylis substituted with R⁷. In another class of the embodiments of thepresent invention, one of R¹ and R² is —C₁₋₆alkyl, wherein alkyl issubstituted with one or two substituents independently selected fromR^(L), and wherein alkyl is substituted with R⁷. In another class of theembodiments of the present invention, at least one of R¹ and R² isethyl, wherein ethyl is unsubstituted or substituted with one to threesubstituents independently selected from R^(L), and wherein one ethyl issubstituted with R⁷. In another class of the embodiments of the presentinvention, one of R¹ and R² is ethyl, wherein ethyl is unsubstituted orsubstituted with one to three substituents independently selected fromR^(L), and wherein ethyl is substituted with R⁷. In another class of theembodiments of the present invention, one of R¹ and R² is ethyl, whereinethyl is substituted with one or two substituents independently selectedfrom R^(L), and wherein ethyl is substituted with R⁷.

In another embodiment, R³ is absent or when present is selected from thegroup consisting of: hydrogen, halogen, —OR^(e), —CN, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, and C₃₋₆cycloalkyl-C₁₋₃alkyl-, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(i). In another embodiment of the presentinvention, R³ is absent or selected from the group consisting of:hydrogen, halogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstitutedor substituted with one to three substituents selected from R¹. Inanother embodiment of the present invention, R³ is absent or selectedfrom the group consisting of: hydrogen, and halogen, wherein each alkylis unsubstituted or substituted with one to three substituents selectedfrom R¹. In another embodiment of the present invention, R³ is absent.In another embodiment of the present invention, R³ is absent orhydrogen. In another embodiment of the present invention, R³ ishydrogen. In another embodiment of the present invention, R³ is absentor halogen. In another embodiment of the present invention, R³ ishalogen.

In another embodiment of the present invention, R³ is absent or—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents selected from R¹. In another embodiment of thepresent invention, R³ is —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from R¹.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of: hydrogen, halogen, OR^(e), C₀₋₅alkylNR^(c)R^(d),C₁₋₆alkyl, and C₁₋₆alkyl-O—, wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(j), providedthat when R⁴ is selected from the group consisting of: OR^(e),C₀alkyl-NR^(c)R^(d), and C₁₋₆alkyl-O—, then X is selected from the groupconsisting of: —CR⁹R⁹, C═O, and —C(R⁹)OC₁₋₆alkyl. In another embodimentof the present invention, R⁴ is selected from the group consisting of:hydrogen, halogen, —C₀₋₅alkylNR^(c)R^(d), and —C₁₋₆alkyl, wherein alkylis unsubstituted or substituted with one to three substituents selectedfrom R^(j), provided that when R⁴ is selected from the group consistingof: —C₀alkyl-NR^(c)R^(d), then X is selected from the group consistingof: —CR⁹R⁹, C═O, and —C(R⁹)OC₁₋₆alkyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of: hydrogen, halogen, and C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(j). In another embodiment of the present invention, R⁴ isselected from the group consisting of: hydrogen, and C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsselected from R^(j). In another embodiment of the present invention, R⁴is hydrogen. In another embodiment of the present invention, R⁴ is—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents selected from R^(j).

In another embodiment of the present invention, R⁵ is absent or whenpresent R⁵ is selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom R¹. In another embodiment of the present invention, R⁵ is absent orselected from the group consisting of: hydrogen, and —C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsselected from R^(j). In another embodiment of the present invention, R⁵is absent. In another embodiment of the present invention, R⁵ is absentor hydrogen. In another embodiment of the present invention, R⁵ ishydrogen. In another embodiment of the present invention, R⁵ is absentor —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents selected from R^(j). In another embodiment of thepresent invention, R⁵ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents selected from R^(j). In another embodiment of thepresent invention, R⁵ is —C₁₋₆alkyl.

In another embodiment of the present invention, R⁶ is absent, or whenpresent R⁶ is selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(j). In another embodiment of the present invention, R⁶ is absentor selected from the group consisting of: hydrogen, and —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(j). In another embodiment of the presentinvention, R⁶ is absent. In another embodiment of the present invention,R⁶ is absent or hydrogen. In another embodiment of the presentinvention, R⁶ is hydrogen. In another embodiment of the presentinvention, R⁶ is absent or —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(j). Inanother embodiment of the present invention, R⁶ is —C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsselected from R^(j). In another embodiment of the present invention, R⁶is —C₁₋₆alkyl.

In another embodiment of the present invention, R⁷ is —CO₂R⁸. In a classof this embodiment, R⁷ is —CO₂H.

In another embodiment of the present invention, R⁸ is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, whereineach alkyl, and cycloalkyl is unsubstituted or substituted with one tothree substituents selected from R^(j). In another embodiment of thepresent invention, R⁸ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from R^(j). In anotherembodiment of the present invention, R⁸ is hydrogen. In anotherembodiment of the present invention, R⁸ is —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(j). In another embodiment of the present invention, R⁸ is—C₁₋₆alkyl.

In another embodiment of the present invention, R⁹ is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, halogen, —(CH₂)₀₋₅OH,—(CH₂)₀₋₅OC₁₋₆alkyl, and —(CH₂)₀₋₆NR^(c)R^(d), wherein each CH₂ isunsubstituted or substituted with one or two substituents selected fromR^(j), and alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(j). In another embodiment of the presentinvention, R⁹ is selected from the group consisting of: hydrogen,—C₁₋₆alkyl, halogen, and —(CH₂)₀₋₆ NR^(c)R^(d), wherein each CH₂ isunsubstituted or substituted with one or two substituents selected fromR^(j), and alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(j). In another embodiment of the presentinvention, R⁹ is selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and halogen, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from R^(j). In anotherembodiment of the present invention, R⁹ is selected from the groupconsisting of: hydrogen, and halogen. In another embodiment of thepresent invention, R⁹ is selected from the group consisting of:hydrogen, and F. In another embodiment of the present invention, R⁹ ishydrogen. In another embodiment of the present invention, R⁹ is—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents selected from R^(j). In another embodiment of thepresent invention, R⁹ is halogen.

In another embodiment of the present invention, R^(a) is selected fromthe group consisting of: —C₁₋₆alkyl, halogen, —C₀₋₆alkyl-OR^(e),—C₀₋₆alkyl-NR^(c)S(O)_(n)R^(e), —C₀₋₆alkyl-S(O)_(n)R^(e),—C₀₋₆alkyl-S(O)_(n)NR^(c)R^(d), —C₀₋₆alkyl-NR^(c)R^(d),—C₀₋₆alkyl-C(O)R^(e), —C₀₋₆alkyl-OC(O)R^(e), —C₀₋₆alkyl-CO₂R^(e),—C₀₋₆alkyl-CN, —C₀₋₆alkyl-C(O)NR^(c)R^(d), —C₀₋₆alkyl-NR^(c)C(O)R^(e),—C₀₋₆alkyl-NR^(c)C(O)OR^(e), —C₀₋₆alkyl-NR^(c)C(O)NR^(c)R^(d), —CF₃,—OCF₃, —OCHF₂, aryl, heteroaryl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl,and —C₂₋₁₀cycloheteroalkyl, wherein each alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to five substituents independently selected from:—C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, —CN, —OCHF₂,—OCF₃, —CF₃, and —C₀₋₆alkyl-NR^(c)R^(d);

In another embodiment of the present invention, R^(a) is selected fromthe group consisting of: —C₁₋₆alkyl, halogen, —C₀₋₆alkyl-OR^(e),—C₀₋₆alkyl-NR^(c)S(O)_(n)R^(e), —C₀₋₆alkyl-S(O)_(n)R^(e),—C₀₋₆alkyl-S(O)_(n)NR^(c)R^(d), —C₀₋₆alkyl-NR^(c)R^(d),—C₀₋₆alkyl-C(O)R^(e), —C₀₋₆alkyl-OC(O)R^(e), —C₀₋₆alkyl-CO₂R^(e),—C₀₋₆alkyl-CN, —C₀₋₆alkyl-C(O)NR^(c)R^(d), —C₀₋₆alkyl-NR^(c)C(O)R^(e),—C₀₋₆alkyl-NR^(c)C(O)OR^(e), —C₀₋₆alkyl-NR^(c)C(O)NR^(c)R^(d), —CF₃,—OCF₃, and —OCHF₂, wherein each alkyl is unsubstituted or substitutedwith one to five substituents independently selected from: —C₁₋₆alkyl,halogen, OH, —O—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, —CN, —OCHF₂, —OCF₃, —CF₃,and —C₀₋₆alkyl-NR^(c)R^(d). In another embodiment of the presentinvention, R^(a) is selected from the group consisting of: —C₁₋₆alkyl,halogen, —OR^(e), —C₀₋₆alkyl-NR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e),—CO₂R^(e), —CN, —CF₃, —OCF₃, and —OCHF₂, wherein each alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: —C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl,—CN, —OCHF₂, —OCF₃, —CF₃, and —C₀₋₆alkyl-NR^(c)R^(d).

In another embodiment of the present invention, R^(a) is selected fromthe group consisting of: —C₁₋₆alkyl, halogen, —OR^(e),—C₀₋₅alkyl-NR^(c)R^(d), —CN, —CF₃, —OCF₃, and —OCHF₂, wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: —C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl and —CF₃. Inanother embodiment of the present invention, R^(a) is selected from thegroup consisting of: —C₁₋₆alkyl, and halogen, wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: —C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl and —CF₃. Inanother embodiment of the present invention, R^(a) is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to fivesubstituents independently selected from: —C₁₋₆alkyl, halogen, OH,—O—C₁₋₆alkyl and —CF₃. In another embodiment of the present invention,R^(a) is halogen. In a class of this embodiment, R^(a) is F.

In another embodiment of the present invention, R^(b) is selected fromthe group consisting of: —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —CF₃, halogen, —CN,—OH, —OC₁₋₁₀alkyl, —OC₂₋₁₀alkenyl, —O(CH₂)pOC₁₋₁₀alkyl,—O(CH₂)pNR^(c)S(O)_(m)R^(e), —O(CH₂)pS(O)_(m)R^(e),—O(CH₂)pS(O)_(m)NR^(c)R^(d), —O(CH₂)pNR^(c)R^(d), —C(O)R^(e),—OC(O)R^(e), —CO₂R^(e), —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e),—NR^(c)C(O)OR^(e), —NR^(c)C(O)NR^(c)R^(d), —OCF₃, and —OCHF₂, whereineach CH, CH₂, alkyl, and alkenyl is unsubstituted or substituted withone to five substituents independently selected from: —C₁₋₆alkyl,halogen, OH, —O—C₁₋₆alkyl and —CF₃. In another embodiment of the presentinvention, R^(b) is selected from the group consisting of: —C₁₋₁₀alkyl,—CF₃, halogen, —CN, —OH, —OC₁₋₁₀alkyl, —O(CH₂)pOC₁₋₁₀alkyl,—O(CH₂)pNR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e), —CO₂R^(e), —OCF₃, and—OCHF₂, wherein each CH, CH₂, alkyl, and alkenyl is unsubstituted orsubstituted with one to five substituents independently selected from:—C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl and —CF₃.

In another embodiment of the present invention, R^(b) is selected fromthe group consisting of: —C₁₋₁₀alkyl, —CF₃, halogen, —CN, —OH,—OC₁₋₁₀alkyl, —OCF₃, and —OCHF₂, wherein each CH, and alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: —C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl and —CF₃. Inanother embodiment of the present invention, R^(b) is selected from thegroup consisting of: —C₁₋₁₀alkyl, —CF₃, halogen, and —OC₁₋₁₀alkyl,wherein each alkyl is unsubstituted or substituted with one to fivesubstituents independently selected from: —C₁₋₆alkyl, halogen, OH,—O—C₁₋₆alkyl and —CF₃. In a class of this embodiment, R^(b) is selectedfrom the group consisting of: —CH₃, —CF₃, F, and —OCH₃. In another classof this embodiment, R^(b) is selected from the group consisting of: Fand —OCH₃.

In another embodiment of the present invention, R^(c) and R^(d) are eachindependently selected from the group consisting of: hydrogen,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-,C₂₋₅cycloheteroalkyl, C₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl-, aryl,heteroaryl, aryl-C₁₋₁₀alkyl-, and heteroaryl-C₁₋₁₀alkyl-, wherein eachalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from R^(f). In another embodiment of the presentinvention, R^(c) and R^(d) are each independently selected from thegroup consisting of: hydrogen, C₁₋₁₀alkyl, and C₂₋₁₀alkenyl, whereineach alkyl, and alkenyl is unsubstituted or substituted with one tothree substituents independently selected from R^(f). In anotherembodiment of the present invention, R^(c) and R^(d) are eachindependently selected from the group consisting of: hydrogen, andC₁₋₁₀alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents independently selected from R^(f). In anotherembodiment of the present invention, R^(c) and R^(d) are each hydrogen.In another embodiment of the present invention, R^(c) and R^(d) are eachindependently selected from the group consisting of: C₁₋₁₀alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsindependently selected from R^(f). In another embodiment of the presentinvention, R^(c) and R^(d) are each independently selected from thegroup consisting of: C₁₋₁₀alkyl.

In another embodiment of the present invention, R^(c) is selected fromthe group consisting of: hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-, C₂₋₅cycloheteroalkyl,C₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl-, aryl, heteroaryl, aryl-C₁₋₁₀alkyl-,and heteroaryl-C₁₋₁₀alkyl-, wherein each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to three substituents independently selected from R^(f). Inanother embodiment of the present invention, R^(c) is selected from thegroup consisting of: hydrogen, C₁₋₁₀alkyl, and C₂₋₁₀alkenyl, whereineach alkyl, and alkenyl is unsubstituted or substituted with one tothree substituents independently selected from R^(f). In anotherembodiment of the present invention, R^(c) is selected from the groupconsisting of: hydrogen, and C₁₋₁₀alkyl, wherein alkyl is unsubstitutedor substituted with one to three substituents independently selectedfrom R^(f). In another embodiment of the present invention, R^(c) ishydrogen. In another embodiment of the present invention, R^(c) is—C₁₋₁₀alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents independently selected from R^(f). In anotherembodiment of the present invention, R^(c) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, R^(d) is selected fromthe group consisting of: hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-, C₂₋₅cycloheteroalkyl,C₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl-, aryl, heteroaryl, aryl-C₁₋₁₀alkyl-,and heteroaryl-C₁₋₁₀alkyl-, wherein each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to three substituents independently selected from R^(f). Inanother embodiment of the present invention, R^(d) is selected from thegroup consisting of: hydrogen, C₁₋₁₀alkyl, and C₂₋₁₀alkenyl, whereineach alkyl and alkenyl is unsubstituted or substituted with one to threesubstituents independently selected from R^(f). In another embodiment ofthe present invention, R^(d) is selected from the group consisting of:hydrogen, and C₁₋₁₀alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents independently selected from R^(f). Inanother embodiment of the present invention, R^(d) is hydrogen. Inanother embodiment of the present invention, R^(d) is —C₁₋₁₀alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents independently selected from R^(f). In another embodiment ofthe present invention, R^(d) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, R^(e) is independentlyselected from the group consisting of: hydrogen, —C₁₋₁₀alkyl, and —C₂₋₁₀alkenyl, wherein each alkyl, and alkenyl is unsubstituted or substitutedwith one to three substituents selected from R^(h). In anotherembodiment of the present invention, each R^(e) is independentlyselected from the group consisting of: hydrogen, and —C₁₋₁₀alkyl,wherein alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(h). In another embodiment of the presentinvention, R^(e) is hydrogen. In another embodiment of the presentinvention, each R^(e) is —C₁₋₁₀alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(h). Inanother embodiment of the present invention, each R^(e) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₁₀alkyl, —OH, —O—C₁₋₄alkyl,—CN, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, C₁₋₆alkyl, cyano and S(O)₂C₁₋₆alkyl. In another embodimentof the present invention, each R^(f) is selected from the groupconsisting of: halogen, —C₁₋₁₀alkyl, —CN, and —CF₃, wherein alkyl isunsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, C₁₋₆alkyl, cyano andS(O)₂C₁₋₆alkyl.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, and C₁₋₁₀alkyl, wherein alkyl isunsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, C₁₋₆alkyl, cyano andS(O)₂C₁₋₆alkyl. In another embodiment of the present invention, eachR^(f) is selected from the group consisting of: halogen. In anotherembodiment of the present invention, each R^(f) is —C₁₋₁₀alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, C₁₋₆alkyl, cyano andS(O)₂C₁₋₆alkyl. In another embodiment of the present invention, eachR^(f) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, each R^(g) isindependently selected from the group consisting of: hydrogen, and—C₁₋₁₀alkyl, wherein alkyl is unsubstituted or substituted with one tofive halogens. In another embodiment of the present invention, R^(g) ishydrogen. In another embodiment of the present invention, each R^(g) is—C₁₋₁₀alkyl, wherein alkyl is unsubstituted or substituted with one tofive halogens. In another embodiment of the present invention, eachR^(g) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, each R^(h) isindependently selected from the group consisting of: halogen,—C₁₋₁₀alkyl, —OH, —O—C₁₋₄alkyl, —CN, —CF₃, —OCHF₂, and —OCF₃, whereinalkyl is unsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, C₁₋₆alkyl, cyano andS(O)₂C₁₋₆alkyl. In another embodiment of the present invention, eachR^(h) is independently selected from the group consisting of: halogen,—C₁₋₁₀alkyl, —CN, and —CF₃, wherein alkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, C₁₋₆alkyl, cyano and S(O)₂C₁₋₆alkyl.

In another embodiment of the present invention, each R^(h) isindependently selected from the group consisting of: halogen, andC₁₋₁₀alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents independently selected from: —OH, halogen, C₁₋₆alkyl,cyano and S(O)₂C₁₋₆alkyl. In another embodiment of the presentinvention, each R^(h) is independently selected from the groupconsisting of: halogen. In another embodiment of the present invention,each R^(h) is —C₁₋₁₀alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents independently selected from: —OH,halogen, C₁₋₆alkyl, cyano and S(O)₂C₁₋₆alkyl. In another embodiment ofthe present invention, each R^(h) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, each R^(i) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OR^(e), —NR^(c)S(O)_(m)R^(e), halogen, —S(O)_(m)R^(e),—S(O)_(m)NR^(c)R^(d), —NR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e), —CO₂R^(e),—CN, —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —CF₃, —OCF₃, and —OCHF₂. In another embodimentof the present invention, each R^(i) is independently selected from thegroup consisting of: —C₁₋₆alkyl, —OR^(e), halogen, —S(O)_(m)R^(e),—NR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e), —CO₂R^(e), —CN, —CF₃, —OCF₃, and—OCHF₂. In another embodiment of the present invention, each R^(i) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OR^(e), halogen, —NR^(c)R^(d), —CN, —CF₃, —OCF₃, and —OCHF₂. In anotherembodiment of the present invention, each R^(i) is independentlyselected from the group consisting of: —C₁₋₆alkyl, and halogen. Inanother embodiment of the present invention, each R^(i) is independentlyselected from the group consisting of: halogen. In another embodiment ofthe present invention, each R^(i) is independently selected from thegroup consisting of: —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(j) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OR^(e), —NR^(c)S(O)_(m)R^(e), halogen, —S(O)_(m)R^(e),—S(O)_(m)NR^(c)R^(d), —NR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e), —CO₂R^(e),—CN, —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —CF₃, —OCF₃, and —OCHF₂. In another embodimentof the present invention, each R^(j) is independently selected from thegroup consisting of: —C₁₋₆alkyl, —OR^(e), halogen, —S(O)_(m)R^(e),—NR^(c)R^(d), —C(O)R^(e), —OC(O)R^(e), —CO₂R^(e), —CN, —CF₃, —OCF₃, and—OCHF₂. In another embodiment of the present invention, each R^(j) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OR^(e), halogen, —NR^(c)R^(d), —CN, —CF₃, —OCF₃, and —OCHF₂. In anotherembodiment of the present invention, each R^(j) is independentlyselected from the group consisting of: —C₁₋₆alkyl, and halogen. Inanother embodiment of the present invention, each R^(j) is halogen. Inanother embodiment of the present invention, each R^(j) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(k) isindependently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, —CF₃, and —CHF₂, wherein alkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, —OC₁₋₆alkyl, halogen, cyano, and —S(O)₂C₁₋₆alkyl. In anotherembodiment of the present invention, each R^(k) is independentlyselected from the group consisting of: hydrogen, and —C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three substituentsindependently selected from: —OH, —OC₁₋₆alkyl, halogen, cyano, and—S(O)₂C₁₋₆alkyl. In another embodiment of the present invention, R^(k)is hydrogen. In another embodiment of the present invention, each R^(k)is —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree substituents independently selected from: —OH, —OC₁₋₆alkyl,halogen, cyano, and —S(O)₂C₁₋₆alkyl. In another embodiment of thepresent invention, each R^(k) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(L) isindependently selected from the group consisting of: —CO₂C₁₋₆alkyl,—C₁₋₁₀alkyl, —C₂₋₁₀ alkenyl, —C₂₋₁₀alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and cycloheteroalkyl is unsubstituted or substituted with one to foursubstituents independently selected from —C₁₋₆alkyl, halogen, and—OC₁₋₆alkyl. In another embodiment of the present invention, each R^(L)is independently selected from the group consisting of: —CO₂C₁₋₆alkyl,—C₁₋₁₀alkyl, —C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein eachalkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substitutedwith one to four substituents independently selected from C₁₋₆alkyl,halogen, and —OC₁₋₆alkyl. In another embodiment of the presentinvention, each R^(L) is independently selected from the groupconsisting of: —C₁₋₁₀alkyl, —C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl,wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to four substituents independently selected fromC₁₋₆alkyl, halogen, and —OC₁₋₆alkyl.

In another embodiment of the present invention, each R^(L) isindependently selected from the group consisting of: —C₁₋₁₀alkyl, and—C₃₋₆cycloalkyl, wherein each alkyl, and cycloalkyl is unsubstituted orsubstituted with one to four substituents independently selected from—C₁₋₆alkyl, halogen, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, each R^(L) is independently selected from the groupconsisting of: —CH₃, cyclobutyl and -cyclopropyl. In another embodimentof the present invention, each R^(L) is independently selected from thegroup consisting of: —CH₃, and -cyclopropyl. In another embodiment ofthe present invention, each R^(L) is —C₁₋₁₀alkyl, wherein alkyl isunsubstituted or substituted with one to four substituents independentlyselected from C₁₋₆alkyl, halogen, and —OC₁₋₆alkyl. In another embodimentof the present invention, each R^(L) is —CH₃. In another embodiment ofthe present invention, each R^(L) is independently selected from thegroup consisting of: —C₃₋₆cycloalkyl, wherein cycloalkyl isunsubstituted or substituted with one to four substituents independentlyselected from C₁₋₆alkyl, halogen, and —OC₁₋₆alkyl. In another embodimentof the present invention, each R^(L) is independently selected from thegroup consisting of: cyclobutyl and -cyclopropyl. In another embodimentof the present invention, each R^(L) is -cyclopropyl. In anotherembodiment of the present invention, each R^(L) is cyclobutyl.

In another embodiment of the present invention, each R^(m) isindependently selected from the group consisting of: —C₁₋₁₀alkyl, and—C₂₋₁₀ alkenyl. In another embodiment of the present invention, eachR^(m) is —C₁₋₁₀alkyl.

In another embodiment of the present invention, n is 0, 1 or 2. In aclass of this embodiment, n is 0 or 1. In another class of thisembodiment, n is 1 or 2. In another class of this embodiment, n is 0. Inanother class of this embodiment, n is 1. In another class of thisembodiment, n is 2.

In another embodiment of the present invention, m is 0, 1 or 2. In aclass of this embodiment, m is 0 or 1. In another class of thisembodiment, m is 1 or 2. In another class of this embodiment, m is 0. Inanother class of this embodiment, m is 1. In another class of thisembodiment, m is 2.

In another embodiment of the present invention, each p is independentlyselected from: 0, 1, 2, 3, 4, 5 or 6. In another embodiment of thepresent invention, p is 0, 1, 2, 3 or 4. In a class of this embodiment,p is 0, 1, 2 or 3. In a class of this embodiment, p is 0, 1 or 2. Inanother embodiment of the present invention, p is 1, 2, 3 or 4. In aclass of this embodiment, p is 1, 2 or 3. In a class of this embodiment,p is 1 or 2. In another class of this embodiment, p is 0 or 1. Inanother class of this embodiment, p is 0 or 2. In another class of thisembodiment, p is 0. In another class of this embodiment, p is 1. Inanother class of this embodiment, p is 2. In another class of thisembodiment, p is 3. In another class of this embodiment, p is 4. Inanother class of this embodiment, p is 5. In another class of thisembodiment, p is 6.

In another embodiment of the present invention, each r is independentlyselected from: 0, 1, 2 or 3. In a class of this embodiment, r is 0, 1 or2. In another class of this embodiment, r is 1, 2 or 3. In a class ofthis embodiment, r is 1 or 2. In another class of this embodiment, r is0 or 1. In another class of this embodiment, r is 0 or 2. In anotherclass of this embodiment, r is 0 or 1. In another class of thisembodiment, r is 1 or 3. In another class of this embodiment, r is 2 or3. In another class of this embodiment, r is 0 or 2. In another class ofthis embodiment, r is 0. In another class of this embodiment, r is 1. Inanother class of this embodiment, r is 2. In another class of thisembodiment, r is 3.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Id:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ie:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula If:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ig:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ih:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ii:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ij:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ik:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Il:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Im:

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I includes the compounds ofstructural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il andIm, and pharmaceutically acceptable salts, hydrates and solvatesthereof.

Another embodiment of the present invention relates to compounds ofstructural formula Ia:

wherein

-   “a” is a single bond;-   Q is —CR⁴R⁶;-   X is —CR⁹R⁹;-   Y is —CR⁹R⁹;-   Z is oxygen;    A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl, and

(3) C₂₋₅ cycloheteroalkyl,

wherein each aryl, heteroaryl and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(a);

B is selected from the group consisting of:

(1) aryl,

(2) aryl-C₁₋₁₀ alkyl-, and

(3) heteroaryl,

wherein each alkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to five substituents selected from R^(b);

R¹ and R² are each independently selected from:

(1) hydrogen, and

(2) —C₁₋₆alkyl,

wherein one of R¹ and R² is —C₁₋₆alkyl substituted with R⁷, and whereinalkyl is unsubstituted or substituted with one to three substituentsindependently selected from R^(L);

-   R³ is absent or hydrogen;-   R⁴ is hydrogen;-   R⁵ is absent or hydrogen;-   R⁶ is absent or hydrogen;-   R⁷ is —CO₂R⁸;-   R⁸ is hydrogen;-   R⁹ is hydrogen;    each R^(L) is independently selected from the group consisting of:    —C₁₋₁₀alkyl, and —C₃₋₆cycloalkyl,    wherein each alkyl, and cycloalkyl is unsubstituted or substituted    with one to four substituents independently selected from C₁₋₆alkyl,    halogen, and —OC₁₋₆alkyl; and    each r is independently selected from: 0, 1, 2 or 3;    or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural Formula Ia:

-   wherein-   “a” is a single bond;-   Q is —CR⁴R⁶;-   X is —CR⁹R⁹;-   Y is —CR⁹R⁹;-   Z is oxygen;    A is selected from the group consisting of:

(1) phenyl,

(2) pyridyl, and

(3) azetidine,

wherein each phenyl, pyridyl and azetidine is unsubstituted orsubstituted with one to four substituents selected from R^(a);

B is selected from the group consisting of:

(1) phenyl,

(2) —CH₂-phenyl, and

(3) pyridyl,

wherein each phenyl and pyridyl is unsubstituted or substituted with oneto five substituents selected from R^(b);

R¹ and R² are each independently selected from:

(1) hydrogen, and

(2) ethyl,

wherein one of R¹ and R² is ethyl substituted with R⁷, and wherein ethylis unsubstituted or substituted with one to three substituentsindependently selected from R^(L);

-   R³ is absent or hydrogen;-   R⁴ is hydrogen;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   R⁷ is —CO₂R⁸;-   R⁸ is hydrogen;-   R⁹ is hydrogen;    each R^(L) is independently selected from the group consisting of:    —CH₃, and -cyclopropyl; and    each r is independently selected from: 0, 1, 2 or 3;    or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as agonists of G-protein-coupled receptor 40(GPR40) are the following compounds:

and pharmaceutically acceptable salts thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating GPR40 mediateddiseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein. Where a stereochemical center isnot defined, the structure represents a mixture of stereoisomers at thatcenter. For such compounds, the individual stereoisomers, includingenantiomers, diastereoisomers, and mixtures of these are also compoundsof the invention.

Definitions

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. The term —C₂alkyl is ethyl. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. In oneembodiment of the present invention, alkyl is methyl. In anotherembodiment of the present invention, alkyl is ethyl.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated monocyclic, bicyclic or bridgedcarbocyclic ring, having a specified number of carbon atoms. The termmay also be used to describe a carbocyclic ring fused to an aryl group.Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like. In one embodiment of the present invention,cycloalkyl is cyclopropane.

“Cycloalkenyl” means a nonaromatic monocyclic or bicyclic carbocylicring containing at least one double bond. Examples of cycloalkenylinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooxtenyl and the like.

“Cycloheteroalkyl” means a saturated monocyclic, bicyclic or bridgedcarbocyclic ring or ring system containing at least one ring heteroatomselected from N, NH, S (including SO and SO₂) and O. Thecycloheteroalkyl ring may be substituted on the ring carbons and/or thering nitrogen(s). Examples of cycloheteroalkyl include tetrahydrofuran,pyrrolidine, tetrahydrothiophene, azetidine, piperazine, piperidine,morpholine, oxetane and tetrahydropyran. In one embodiment of thepresent invention, cycloheteroalkyl is azetidine.

“Cycloheteroalkenyl” means a nonaromatic monocyclic, bicyclic or bridgedcarbocyclic ring or ring system containing at least one double bond andcontaining at least one heteroatom selected from N, NH, S (including SOand SO₂) and O.

“Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromaticring or ring system containing 5-14 carbon atoms, wherein at least oneof the rings is aromatic. Examples of aryl include phenyl and naphthyl.In one embodiment of the present invention, aryl is phenyl.

“Heteroaryl” means monocyclic, bicyclic or tricyclic ring or ring systemcontaining 5-14 carbon atoms and containing at least one ring heteroatomselected from N, NH, S (including SO and SO₂) and O, wherein at leastone of the heteroatom containing rings is aromatic. Examples ofheteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl,pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, benzpyrazole (or indazole),benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl,quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and thelike. In one embodiment of the present invention, heteroaryl ispyridine.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment of the present invention, halogen is bromine, chlorine orfluorine. In another embodiment of the present invention, halogen ischlorine or fluorine. In another embodiment of the present invention,halogen is bromine. In another embodiment of the present invention,halogen is chlorine. In another embodiment of the present invention,halogen is fluorine.

“Me” represents methyl.

“Oxo” is ═O.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

For example, —NR^(c)C(O)R^(e) is equivalent to —N(R^(c))C(O)R^(e).

Unless expressly depicted or described otherwise, substituents depictedin a structural formula with a “floating” bond, such as but not limitedto R³, is permitted on any available carbon atom in the ring to whichthe substituent is attached. In one embodiment of the present invention,R³ may be substituted on any CH in the ring to which R³ is attached.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

The term “% enantiomeric excess” (abbreviated “ee”) shall mean the %major enantiomer less the % minor enantiomer. Thus, a 70% enantiomericexcess corresponds to formation of 85% of one enantiomer and 15% of theother. The term “enantiomeric excess” is synonymous with the term“optical purity.”

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Salts:

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of thepresent invention are included in the present invention as well.

Utilities

The compounds of the present invention are potent agonists of the GPR40receptor. The compounds, and pharmaceutically acceptable salts thereof,may be efficacious in the treatment of diseases that are modulated byGPR40 ligands, which are generally agonists. Many of these diseases aresummarized below.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, to a patient in need oftreatment. Also, the compounds of the present invention may be used forthe manufacture of a medicament which may be useful for treating one ormore of these diseases: (1) non-insulin dependent diabetes mellitus(Type 2 diabetes); (2) hyperglycemia; (3) insulin resistance; (4)Metabolic Syndrome; (5) obesity; (6) hypercholesterolemia; (7)hypertriglyceridemia (elevated levels oftriglyceride-rich-lipoproteins); (8) mixed or diabetic dyslipidemia; (9)low HDL cholesterol; (10) high LDL cholesterol; (11) hyperapo-Bliproteinemia; and (12) atherosclerosis.

Preferred uses of the compounds may be for the treatment of one or moreof the following diseases by administering a therapeutically effectiveamount to a patient in need of treatment. The compounds may be used formanufacturing a medicament for the treatment of one or more of thesediseases: (1) Type 2 diabetes, and specifically hyperglycemia associatedwith Type 2 diabetes; (2) Metabolic Syndrome; (3) obesity; and (4)hypercholesterolemia.

The compounds may be effective in lowering glucose and lipids indiabetic patients and in non-diabetic patients who have impaired glucosetolerance and/or are in a pre-diabetic condition. The compounds mayameliorate hyperinsulinemia, which often occurs in diabetic orpre-diabetic patients, by modulating the swings in the level of serumglucose that often occurs in these patients. The compounds may also beeffective in treating or reducing insulin resistance. The compounds maybe effective in treating or preventing gestational diabetes.

The compounds may also be effective in treating or preventing lipiddisorders. The compounds may be effective in treating or preventingdiabetes related disorders. The compounds may also be effective intreating or preventing obesity related disorders.

The compounds of this invention may also have utility in improving orrestoring β-cell function, so that they may be useful in treating Type 1diabetes or in delaying or preventing a patient with Type 2 diabetesfrom needing insulin therapy.

The invention also includes pharmaceutically acceptable salts of thecompounds, and pharmaceutical compositions comprising the compounds anda pharmaceutically acceptable carrier. The compounds may be useful intreating insulin resistance, Type 2 diabetes, hyperglycemia, anddyslipidemia that is associated with Type 2 diabetes and insulinresistance. The compounds may also be useful for the treatment ofobesity

A compound of the present invention, or a pharmaceutically acceptablesalt thereof, may be used in the manufacture of a medicament for thetreatment of Type 2 diabetes in a human or other mammalian patient.

A method of treating Type 2 diabetes comprises the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound, to a human or other mammaliansubject or patient in need of treatment. Other medical uses of thecompounds of the present invention are described herein.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type 2 diabetics are also obese. The compositions of thepresent invention may be useful for treating both Type 1 and Type 2diabetes. The term “diabetes associated with obesity” refers to diabetescaused by obesity or resulting from obesity.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. A pre diabeticsubject is someone suffering from prediabetes. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of ≥140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat a diabeticsubject. One outcome of treatment may be decreasing the glucose level ina subject with elevated glucose levels. Another outcome of treatment maybe decreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensivity. Another outcome of treatmentmay be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to meandisorders that are associated with, caused by, or result from diabetes.Examples of diabetes related disorders include retinal damage, kidneydisease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of a GPR40 agonist incombination with a therapeutically effective amount of ananti-hypertensive agent may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists. Theterm “atherosclerosis related disorders” should be understood to meandisorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (≥140 mmHg/≥90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as less than 120 mmHg systolic and less than 80 mmHg diastolic.A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg. One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecompounds and combinations of the present invention to treathypertension in a hypertensive subject. Treatment ofhypertension-related disorder refers to the administration of a compoundor combination of the present invention to treat thehypertension-related disorder. Prevention of hypertension, or ahypertension related disorder, refers to the administration of thecombinations of the present invention to a pre-hypertensive subject toprevent the onset of hypertension or a hypertension related disorder.The hypertension-related disorders herein are associated with, causedby, or result from hypertension. Examples of hypertension-relateddisorders include, but are not limited to: heart disease, heart failure,heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolismincluding various conditions characterized by abnormal concentrations ofone or more lipids (i.e. cholesterol and triglycerides), and/orapolipoproteins (i.e., apolipoproteins A, B, C and E), and/orlipoproteins (i.e., the macromolecular complexes formed by the lipid andthe apolipoprotein that allow lipids to circulate in blood, such as LDL,VLDL and IDL). Hyperlipidemia is associated with abnormally high levelsof lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment ofdyslipidemia refers to the administration of the combinations of thepresent invention to a dyslipidemic subject. Prevention of dyslipidemiarefers to the administration of the combinations of the presentinvention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is asubject with higher than normal lipid levels, that is not yetdyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder relateddisorders” should be understood to mean disorders associated with,caused by, or resulting from dyslipidemia or lipid disorders. Examplesof dylipidemia related disorder and lipid disorder related disordersinclude, but are not limited to: hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high density lipoprotein (HDL) levels, highplasma low density lipoprotein (LDL) levels, atherosclerosis and itssequelae, coronary artery or carotid artery disease, heart attack, andstroke.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². An overweightsubject is a subject at risk of obesity. A “subject at risk of obesity”is an otherwise healthy subject with a BMI of 25 kg/m² to less than 30kg/m² or a subject with at least one co-morbidity with a BMI of 25 kg/m²to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes mellitus, non-insulin dependent diabetesmellitus—type 2, diabetes associated with obesity, impaired glucosetolerance, impaired fasting glucose, insulin resistance syndrome,dyslipidemia, hypertension, hypertension associated with obesity,hyperuricacidemia, gout, coronary artery disease, myocardial infarction,angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fattyliver; cerebral infarction, cerebral thrombosis, transient ischemicattack, orthopedic disorders, arthritis deformans, lumbodynia,emmeniopathy, and infertility. In particular, co-morbidities include:hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,cardiovascular disease, sleep apnea, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III, or ATP III), National Institutesof Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA,vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined ashaving metabolic syndrome if the person has three or more of thefollowing disorders: abdominal obesity, hypertriglyceridemia, low HDLcholesterol, high blood pressure, and high fasting plasma glucose. Thecriteria for these are defined in ATP-III. Treatment of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with metabolic syndrome. Prevention of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with two of the disorders that define metabolicsyndrome. A subject with two of the disorders that define metabolicsyndrome is a subject that has developed two of the disorders thatdefine metabolic syndrome, but has not yet developed three or more ofthe disorders that define metabolic syndrome.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to a human or other mammal in need oftreatment.

The term “patient” should be understood to mean a human or other mammalin need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringa therapeutically effective amount of the compound of structural formulaI to the mammal (human or other mammal) in need of such treatment orprophylaxis. The need for a prophylactic administration according to themethods of the present invention is determined via the use of well knownrisk factors. The therapeutically effective amount of an individualcompound is determined, in the final analysis, by the physician orveterinarian in charge of the case, but depends on factors such as theexact disease to be treated, the severity of the disease and otherdiseases or conditions from which the patient suffers, the chosen routeof administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with a therapeutically effective dose of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably compounds of the present invention are administered orally.

In the treatment or prevention of conditions which require agonism ofGPR40 receptor activity, an appropriate dosage level will generally beabout 0.01 to 500 mg per kg patient body weight per day which may beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions maypreferably be provided in the form of tablets containing 1.0 to 1000 mgof the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0,50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention may be indicated, generally satisfactory results couldbe obtained when the compounds of the present invention are administeredat a daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the patient undergoing therapy.

The compounds of this invention may be used in pharmaceuticalcompositions comprising (a) the compound(s) or a pharmaceuticallyacceptable salt thereof, and (b) a pharmaceutically acceptable carrier.The compounds of this invention may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this invention may also be used inpharmaceutical compositions in which the compound of the presentinvention or a pharmaceutically acceptable salt thereof is the onlyactive ingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Combination Therapy

The compounds of the present invention may be useful in methods for theprevention or treatment of the aforementioned diseases, disorders andconditions in combination with other therapeutic agents.

The compounds of the present invention may be useful in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of formula Ior the other drugs may have utility, where the combination of the drugstogether are safer, more effective or more therapeutically effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a compound of formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of formula I.

Examples of other active ingredients that may be administered separatelyor in the same pharmaceutical composition in combination with a compoundof the formulas described herein include, but are not limited to: (1)dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin,omarigliptin, trelagliptin, teneligliptin, bisegliptin, anagliptin,vildagliptin, saxagliptin, alogliptin, melogliptin, linagliptin,gosogliptin, evogliptin, and gemigliptin), (2) insulin sensitizers,including (i) PPARγ agonists, such as the glitazones (e.g. pioglitazone,AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone,and balaglitazone), and other PPAR ligands, including (1) PPARα/γ dualagonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar,aleglitazar, sodelglitazar, and naveglitazar); (2) PPARα agonists suchas fenofibric acid derivatives (e.g., gemfibrozil, clofibrate,ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modulators(SPPARγM's), (e.g., such as those disclosed in WO 02/060388, WO02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO2004/066963); and (4) PPARγ partial agonists; (ii) biguanides, such asmetformin and its pharmaceutically acceptable salts, in particular,metformin hydrochloride, and extended-release formulations thereof, suchas Glumetza™, Fortamet™, and GlucophageXR™; and (iii) protein tyrosinephosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); (3)insulin or insulin analogs (e.g., insulin detemir, insulin glulisine,insulin degludec, insulin glargine, insulin lispro and inhalableformulations of each); (4) leptin and leptin derivatives and agonists;(5) amylin and amylin analogs (e.g., pramlintide); (6) sulfonylurea andnon-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide,glipizide, glimepiride, mitiglinide, meglitinides, nateglinide andrepaglinide); (7) α-glucosidase inhibitors (e.g., acarbose, vogliboseand miglitol); (8) glucagon receptor antagonists (e.g., MK-3577,MK-0893, LY-2409021 and KT6-971); (9) incretin mimetics, such as GLP-1,GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists(e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide,lixisenatide, taspoglutide, CJC-1131, and BIM-51077, includingintranasal, transdermal, and once-weekly formulations thereof); (10) LDLcholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin,atorvastatin, pitavastatin and rosuvastatin), (ii) bile acidsequestering agents (e.g., colestilan, colestimide, colesevalamhydrochloride, colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) inhibitors of cholesterolabsorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterolacyltransferase inhibitors, (e.g., avasimibe); (11) HDL-raising drugs,(e.g., niacin and nicotinic acid receptor agonists, and extended-releaseversions thereof; (12) antiobesity compounds; (13) agents intended foruse in inflammatory conditions, such as aspirin, non-steroidalanti-inflammatory drugs or NSAIDs, glucocorticoids, and selectivecyclooxygenase-2 or COX-2 inhibitors; (14) antihypertensive agents, suchas ACE inhibitors (e.g., lisinopril, enalapril, ramipril, captopril,quinapril, and tandolapril), A-II receptor blockers (e.g., losartan,candesartan, irbesartan, olmesartan, medoxomil, valsartan, telmisartan,and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers, andcalcium channel blockers; (15) glucokinase activators (GKAs) (e.g.,AZD6370); (16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1,(e.g., such as those disclosed in U.S. Pat. No. 6,730,690, andLY-2523199); (17) CETP inhibitors (e.g., anacetrapib, evacetrapib,torcetrapib, and AT-03); (18) inhibitors of fructose 1,6-bisphosphatase,(e.g., MB-07803, and such as those disclosed in U.S. Pat. Nos.6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); (19)inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); (20)AMP-activated Protein Kinase (AMPK) activators (e.g., MB-11055); (21)other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii)GPR-119 (e.g., MBX2982 and PSN821), (iii) GPR-40 (e.g., fasiglifam,JTT-851, TAK-875, and P-11187, and (iv) GPR-120 (e.g., KDT-501); (22)SSTR3 antagonists (e.g., pasireotide, and such as those disclosed in WO2009/011836); (23) neuromedin U receptor agonists (e.g., such as thosedisclosed in WO 2009/042053, including, but not limited to, neuromedin S(NMS)); (24) SCD inhibitors; (25) GPR-105 antagonists (e.g., such asthose disclosed in WO 2009/000087); (26) SGLT inhibitors (e.g., LIK-066,ASP1941, SGLT-3, ertugliflozin, empagliflozin, dapagliflozin,canagliflozin, BI-10773, PF-04971729, remogloflozin, luseogliflozin,tofogliflozin, ipragliflozin, and LX-4211); (27) inhibitors of (i) acylcoenzyme A:diacylglycerol acyltransferase 1, DGAT-1 (e.g., pradigastat,and P-7435) and acyl coenzyme A:diacylglycerol acyltransferase 2,DGAT-2; (28) inhibitors of fatty acid synthase; (29) inhibitors of acylcoenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);(30) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR) (eg., sodium taurocholate); (31) ileal bile acidtransporter inhibitors (eg., elobixibat); (32) PACAP, PACAP mimetics,and PACAP receptor 3 agonists; (33) PPAR agonists; (34) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (35) IL-1b antibodies andinhibitors, (e.g., gevokizumab, canakinumab, danazol, AC-201, andBLX-1002); and (36) bromocriptine mesylate and rapid-releaseformulations thereof.

Of particular interest are dipeptidyl peptidase-IV (DPP-4) inhibitorsthat may be useful in combination with compounds of the presentinvention. Such inhibitors include, without limitation, sitagliptin(disclosed in U.S. Pat. No. 6,699,871), omarigliptin, trelagliptin,teneligliptin, bisegliptin, anagliptin, LC15-0444, vildagliptin,saxagliptin, alogliptin, melogliptin, linagliptin, gosogliptin,evogliptin, gemigliptin, and pharmaceutically acceptable salts thereof,and fixed-dose combinations of these compounds with metforminhydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin,or a sulfonylurea.

Other GPR-40 agonists that may be useful in combination with compoundsof the formulas described herein include, but are not limited to: (1)5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-1H-indene-1-yl]oxy]phenyl]isothiazole-3-ol1-oxide; (2)5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)-methoxy)-phenyl)isothiazole-3-ol1-oxide; and (3)5-(4-((3-(2-methyl-6-(3-hydroxypropoxy)-pyridine-3-yl)-2-methylphenyl)methoxy)-phenyl)isothiazole-3-ol1-oxide; and (4)5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]-methoxy]phenyl]isothiazole-3-ol1-oxide, and pharmaceutically acceptable salts thereof.

Antiobesity compounds that may be combined with compounds of formula Iinclude topiramate; zonisamide; naltrexone; phentermine; bupropion; thecombination of bupropion and naltrexone; the combination of bupropionand zonisamide; the combination of topiramate and phentermine;fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such asorlistat and cetilistat; melanocortin receptor agonists, in particular,melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentratinghormone (MCH) receptor antagonists; neuropeptide Y₁ or Y₅ antagonists(such as MK-0557); β₃ adrenergic receptor agonists; CB-1 receptorinverse agonists and antagonists; ghrelin antagonists; bombesin receptoragonists (such as bombesin receptor subtype-3 agonists); and5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For areview of anti-obesity compounds that may be useful in combination witha compound of the present invention, see S. Chaki et al., “Recentadvances in feeding suppressing agents: potential therapeutic strategyfor the treatment of obesity,” Expert Opin. Ther. Patents, 11: 1677-1692(2001); D. Spanswick and K. Lee, “Emerging antiobesity drugs,” ExpertOpin. Emerging Drugs, 8: 217-237 (2003); J. A. Fernandez-Lopez, et al.,“Pharmacological Approaches for the Treatment of Obesity,” Drugs, 62:915-944 (2002); and K. M. Gadde, et al., “Combination pharmaceuticaltherapies for obesity,” Exp. Opin. Pharmacother., 10: 921-925 (2009).

Glucagon receptor antagonists that may be useful in combination with thecompounds of formula I include, but are not limited to: (1)N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;(2)N-[4-((1R)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;(3)N-(4-{1-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;(4)N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;(5)N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-β-alanine;and (6)N-(4-{(1S)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)-β-alanine;and pharmaceutically acceptable salts thereof.

Another embodiment of the present invention relates to a pharmaceuticalcomposition comprising one or more of the following agents: (a) acompound of structural formula I; (b) one or more compounds selectedfrom the group consisting of: (1) dipeptidyl peptidase-IV (DPP-4)inhibitors (e.g., sitagliptin, omarigliptin, trelagliptin,teneligliptin, bisegliptin, anagliptin, vildagliptin, saxagliptin,alogliptin, melogliptin, linagliptin, gosogliptin, evogliptin, andgemigliptin); (2) insulin sensitizers, including (i) PPARγ agonists,such as the glitazones (e.g. AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, pioglitazone, rosiglitazone, and balaglitazone)and other PPAR ligands, including (1) PPARα/γ dual agonists, such asZYH1, YYH2, chiglitazar, GFT505, muraglitazar, aleglitazar,sodelglitazar, and naveglitazar, (2) PPARα agonists, such as fenofibricacid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate,fenofibrate and bezafibrate), (3) selective PPARγ modulators(SPPARγM's), (4) PPARγ partial agonists; (ii) biguanides, such asmetformin and its pharmaceutically acceptable salts, in particular,metformin hydrochloride, and extended-release formulations thereof, suchas Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosinephosphatase-1B (PTP-1B) inhibitors, such as ISI-113715, and TTP814; (3)sulfonylurea and non-sulfonylurea insulin secretagogues, (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, andmeglitinides, such as nateglinide and repaglinide); (4) α-glucosidaseinhibitors (e.g., acarbose, voglibose and miglitol); (5) glucagonreceptor antagonists; (6) LDL cholesterol lowering agents such as (i)HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, androsuvastatin), (ii) bile acid sequestering agents (e.g., colestilan,cholestyramine, colestimide, colesevelam hydrochloride, colestipol, anddialkylaminoalkyl derivatives of a cross-linked dextran), (iii)inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acylCoA:cholesterol acyltransferase inhibitors (e.g., avasimibe); (7)HDL-raising drugs, such as niacin or a salt thereof and extended-releaseversions thereof; and nicotinic acid receptor agonists; (8) antiobesitycompounds; (9) agents intended for use in inflammatory conditions, suchas aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (10)antihypertensive agents, such as ACE inhibitors (e.g., enalapril,lisinopril, ramipril,

captopril, quinapril, and tandolapril), A-II receptor blockers (e.g.,losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan,telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), betablockers (e.g., calcium channel blockers); (11) glucokinase activators(GKAs) (e.g., AZD6370, GKM-001, TMG-123, HMS-5552, DS-7309, PF-04937319,TTP-399, ZYGK-1); (12) inhibitors of 11β-hydroxysteroid dehydrogenasetype 1 (e.g., such as those disclosed in U.S. Pat. No. 6,730,690; WO03/104207; and WO 04/058741); (13) inhibitors of cholesteryl estertransfer protein (CETP), (e.g., torcetrapib, evacetrapib, anacetrapib,and AT-03); (14) inhibitors of fructose 1,6-bisphosphatase (e.g.,MB-07803, and such as those disclosed in U.S. Pat. Nos. 6,054,587;6,110,903; 6,284,748; 6,399,782; and 6,489,476); (15) inhibitors ofacetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); (16) AMP-activated ProteinKinase (AMPK) activators (e.g., MB-11055); (17) agonists of theG-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982,and PSN821), (iii) GPR-40 (e.g., fasiglifam, JTT-851, P-11187,5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-1H-indene-1-yl]oxy]phenyl]isothiazole-3-ol1-oxide,5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)-methoxy)phenyl)-isothiazole-3-ol1-oxide,5-(4-((3-(2-methyl-6-(3-hydroxypropoxy)pyridine-3-yl)-2-methyl-phenyl)methoxy)phenyl)-isothiazole-3-ol1-oxide, and5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]-methoxy]phenyl]isothiazole-3-ol1-oxide), and (iv) GPR-120 (e.g., KDT-501); (18) SSTR3 antagonists(e.g., pasireotide, and such as those disclosed in WO 2009/011836); (19)neuromedin U receptor agonists (e.g., such as those disclosed inWO2009/042053, including, but not limited to, neuromedin S (NMS)); (20)inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (21) GPR-105antagonists (e.g., such as those disclosed in WO 2009/000087); (22)inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT)inhibitors and its various isoforms, such as SGLT-1; SGLT-2 (e.g.,LIK-066, ertuglifozin, ASP1941, luseogliflozin, BI10773, tofogliflozin,LX4211, canagliflozin, dapagliflozin and remogliflozin; and SGLT-3);(23) inhibitors of (i) acyl coenzyme A:diacylglycerol acyltransferase 1,DGAT-1 (e.g., pradigastat, and P-7435) and acyl coenzymeA:diacylglycerol acyltransferase 2, DGAT-2; (24) inhibitors of fattyacid synthase; (25) inhibitors of acyl coenzyme A:monoacylglycerolacyltransferase 1 and 2 (MGAT-1 and MGAT-2); (26) agonists of the TGR5receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR) (eg.,sodium taurocholate); (28) bromocriptine mesylate and rapid-releaseformulations thereof, and (29) IL-1b antibodies and inhibitors (e.g.,gevokizumab, canakinumab, danazol, AC-201, and BLX-1002); and (c) apharmaceutically acceptable carrier.

Specific compounds that may be useful in combination with a compound ofthe present invention include: simvastatin, mevastatin, ezetimibe,atorvastatin, rosuvastatin, sitagliptin, omarigliptin, metformin,sibutramine, orlistat, topiramate, naltrexone, bupriopion, phentermine,losartan, losartan with hydrochlorothiazide, olmesartan, canagliflozin,dapagliflozin, ipragliflozin and ertugliflozin.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds with two or more active compounds selected from biguanides,sulfonylureas, HMG-CoA reductase inhibitors, PPARγ agonists, DPP-4inhibitors, anti-obesity compounds, and anti-hypertensive agents.

The present invention may also provide a method for the treatment orprevention of a G-protein coupled receptor 40 (GPR40) mediated disease,which method comprises administration to a patient in need of suchtreatment or at risk of developing a GPR40 mediated disease of an amountof a GPR40 agonist and an amount of one or more active ingredients, suchthat together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a GPR40 agonist and one or moreactive ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a GPR40 agonist and one or more active ingredientsfor the manufacture of a medicament for the treatment or prevention of aGPR40 mediated disease. In a further or alternative aspect of thepresent invention, there is therefore provided a product comprising aGPR40 agonist and one or more active ingredients as a combinedpreparation for simultaneous, separate or sequential use in thetreatment or prevention of a GPR40 mediated disease. Such a combinedpreparation may be, for example, in the form of a twin pack.

For the treatment or prevention of diabetes, obesity, hypertension,Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and relateddisorders thereof, a compound of the present invention may be used inconjunction with another pharmaceutical agent effective to treat thatdisorder.

The present invention may also provide a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an effective amount of a compound of the present invention andan amount of another pharmaceutical agent effective to threat thatdisorder, such that together they give effective relief.

The present invention may also provide a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, such that together they give effective relief.

The term “therapeutically effective amount” or “a therapeuticallyeffective dose” means the amount the compound of structural formula Ithat will elicit the biological or medical response of a tissue, system,animal, mammal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician, which includesalleviation of the symptoms of the disorder being treated. The novelmethods of treatment of this invention are for disorders known to thoseskilled in the art. The term “mammal” includes, but is not limited to,humans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, a therapeutically effective dose of each will beused. Thus, for example, when a compound of the Formula I is combinedwith a DPIV inhibitor the weight ratio of the compound of the Formula Ito the DPIV inhibitor will generally range from about 1000:1 to about1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the Formula I and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

Methods of Synthesis of the Compounds of the Present Invention:

The following reaction schemes and Examples illustrate methods which maybe employed for the synthesis of the compounds of structural formula Idescribed in this invention. Those skilled in the art will readilyunderstand that known variations of protecting groups, as well as of theconditions and processes of the following preparative procedures, can beused to prepare these compounds. It is also understood that whenever achemical reagent such as a boronic acid or a boronate is notcommercially available, such a chemical reagent can be readily preparedfollowing one of numerous methods described in the literature. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured either by electrospray ion-mass spectroscopy (ESMS)or by atmospheric pressure chemical ionization mass spectroscopy (APCI).All temperatures are degrees Celsius unless otherwise noted.

LIST OF ABBREVIATIONS

Ac is acetyl; AcCN is acetonitrile; AcO is acetoxy; Alk is alkyl; anh.is anhydrous; APCI is atmospheric pressure chemical ionization; aq oraq. is aqueous; Ar is aryl; atm is atmosphere; Boc istert-butoxycarbonyl; Bn—O is phenyl-CH₂—O or benzyloxy; BrettPhospalladacycle precatalyst is Brettphos Pd G1 precatalyst (Aldrich);n-BuLi is n-butyl lithium; Bu₃P is tributylphosphine; t-buxhospalladacycle ischloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II),min. 98% [t-BuXPhos Palladacycle]; t-BuOK is potassium tert-butoxide; °C. is degrees celsius; Cataxium precatalyst or Cataxium Pd precat orprecatalyst is cataCXium A Pd G3 (Aldrich); Cbz is benzyloxycarbonyl;conc or conc. is concentrated; CDI is carbonyldiimidazole; CV is columnvolumes; diatomite is diatomaceous earth or Celite™; DAST is(diethylamino)sulfur trifluoride; DIBAL-H is diisobutylaluminum hydride;DIAD is diisopropyl azodicarboxylate; DCM is dichloromethane; DEA isdiethyl amine; DIPEA is N,N-diisopropylethylamine; DIPA is diisopropylamine; DMAP is 4-dimethyl-aminopyridine; DMF is N,N-dimethylformamide;DMS is dimethyl sulfide; DMSO is dimethylsulfoxide; dppf is1,1′-Bis(diphenyl-phosphino)ferrocene; eq or equiv is equivalent(s); ESIis electrospray ionization; EA or EtOAc is ethyl acetate; Et is ethyl;Et₂O is diethyl ether; EtMgBr is ethyl magnesium bromide; EtOH isethanol; g is gram(s); h or hr or hrs is hour(s); hex is hexanes; HPLCis high pressure liquid chromatography; HOAc or AcOH is acetic acid; kgis kilogram(s); IPA or i-PrOH is isopropanol; KOAc is potassium acetate;KOtBu is potassium tert-butoxide; L is liter; LAH is lithium aluminumhydride; M is molar; LC-MS is liquid chromatography-mass spectroscopy;LDA is lithium diisopropyl amide; Me is methyl; MeO is methoxy; m-CPBA,MCPBA, or mCPBA is meta chloroperbenzoic acid; ml or mL is milliliter;min or mins is minute(s); mol is mole(s); mmol is mmole(s); mg ismilligram(s); MeMgBr is methyl magnesium bromide; MeOH is methyl alcoholor methanol; MPLC is medium pressure liquid chromatography; MPa ismegapascals; MS is mass spectroscopy; MsCl or Ms-Cl is methane sulfonylchloride; MeCN is acetonitrile; MeI is methyl iodide; MsCl is methanesulfonyl chloride; MTBE is methyl tert-butyl ether; MW is molecularweight; NaOMe is sodium methoxide; NaHMDS is sodium hexamethyldisilazide; NH₄OAc is ammonium acetate; NBS is N-bromo succinamide; NEt₃is triethyl amine; NIS is N-iodo succinamide; NMO is 4-methyl morpholineN-oxide; NMP is 1-methyl-2-pyrrolidinone; NMR is nuclear magneticresonance spectroscopy; o.n. or ON is overnight; PE is petroleum ether;PG is protecting group; Pd₂(dba)₃ istris(dibenzylidene-acetone)-dipalladium(0); Pd(OAc)₂ is palladiumacetate; Pd[P(t-Bu)₃]₂ is bis(tri-tert-butylphosphine)-palladium (0);Pd(dppf)Cl₂ is[1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium (II); PdCl₂(dppf)₂CH₂Cl₂ is[1,1′-Bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (Aldrich); Pd(PPh₃)₄ is tetrakis ortetrakis(triphenylphosphine)palladium (0); PPh₃ is triphenyl phosphine;Pd(t-Bu₂P)₂—FerrCl₂ is bis-tri-tert-butylphosphino ferrocene dichloropalladium (II); Pd(OH)₂/C is 20% palladium hydroxide on activated carbon(50 wt. % water) or Pearlman's catalyst; precat is precatalyst; prep ispreparative; prep. TLC or prep-TLC, or prep TCL is preparative thinlayer chromatography; rt or r.t. or RT isroom temperature;RuCl[(R,R)-TSDPEN](mesitylene) is[N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzene-sulfonamidato-κN]chloro-[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium;Ru-Josiphos is generated using (Me-allyl)2Ru(COD) (Aldrich) and JosiphosSL-J502-2 (Aldrich); R_(f) is retention factor; sat or sat. issaturated; SEM is trimethylsilyl ethoxy methyl, SEMCl is trimethylsilylethoxy methyl chloride; SFC is supercritical fluid chromatography;S-Phos is 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl; S-Phos(Pd)ischloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]-palladium(II)[CAS-No. 1028206-58-7]; S-Phos precatalyst is S-Phos Pd G2precatalyst—Aldrich; S-Phos second generation precatalyst isChloro(2-dicyclohexyl-phosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium-(II),SPhos-Pd-G2) [CAS-No. 1375325-64-6]; TBAF is tetrabutylammoniumfluoride; TBSCl is tert-butyl dimethylsilyl chloride; TEA is triethylamine; Tf is trifluoromethane sulfonyl; THF is tetrahydrofuran;Ti(OiPr)₄ is titanium isopropoxide; TFA is trifluoroacetic acid; TLC isthin-layer chromatography; TosCl and TsCl is p-toluene sulfonylchloride; pTSA, pTsOH and TsOH is p-toluenesulfonic acid, Ts₂O is tosicanhydride or p-toluene sulfonic anhydride; xphos is2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl; and vol isvolume(s).

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare either commercially available or made by known procedures in theliterature or as illustrated. The present invention further providesprocesses for the preparation of compounds of structural formula I asdefined above. In some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products. The following Schemes and Examples areprovided to illustrate the invention and are not to be construed aslimiting the invention in any manner. The scope of the invention isdefined by the appended claims.

Scheme 1 provides a route to Intermediate 1. The cyclopropyl β-ketoesterwas methylated and then trapped at the vinyl tosylate. Suzukicross-coupling with m-benzyloxy phenylboronic acid delivered the “Z”enoate. Asymmetric reduction of the double bond was followed bydebenzylation under hydrogen pressure.

Intermediate 1 (2R,3R)-Methyl3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropanoate

Step 1: methyl 3-cyclopropyl-2-methyl-3-oxopropanoate

A slurry of NaH (0.563 g, 60% in mineral oil) in THF (20 mL) was cooledto 10° C., and methyl 3-cyclopropyl-3-oxopropanoate (2 g) was added inportions at room temperature over 30 min. Then MeI (0.88 mL) was addedover 5 min at room temperature and the reaction was stirred at roomtemperature overnight. The reaction was then reverse quenched into ahalf saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL).The aqueous layer was separated and extracted once with 50 mL EtOAc. Theorganic layer was washed with water and brine, and then concentrated togive the title compound, which was used in the next the step withoutfurther purification.

Step 2: (Z)-methyl 3-cyclopropyl-2-methyl-3-(tosyloxy)acrylate

To a solution of methyl 3-cyclopropyl-2-methyl-3-oxopropanoate (5 g) inMTBE (50 mL) was added a 1M solution of NaHMDS in hexane (41 mL), whilekeeping the internal temperature between 18-23° C. The reaction wasstirred at room temperature for 30 min. Then tosic anhydride (10 g) wasslurried in MTBE (200 mL). The reaction mixture was added to the tosicanhydride slurry, while keeping the internal temperature between 19° C.and 24° C. After 30 min, additional tosic anhydride (3.3 g, 0.3 eq) wasadded, and the reaction was stirred for 1 h. Then water (500 mL) andEtOAc (400 mL) were added to the reaction mixture. The aqueous layer wasseparated and extracted once with EtOAc (100 mL) The organic layer wasseparated, washed with water (200 mL) and brine (100 mL), andconcentrated to give the crude product, which was re-crystallized fromMTBE/heptanes (1:1, 50 mL) to give the title compound.

Step 3: (Z)-methyl3-(3-(benzvloxy)phenyl)-3-cyclopropyl-2-methylacrylate

(Z)-methyl 3-cyclopropyl-2-methyl-3-(tosyloxy)acrylate (1.03 g) wasdissolved in MeCN (10 mL), then aqueous potassium phosphate (1 M, 10 mL)was added, followed by the addition of (3-(benzyloxy)phenyl)boronic acid(1 g). The resulting slurry was degassed with a nitrogen stream for 30min, then cataCXium A Pd G3 (Aldrich #761435, 100 mg) was added and thereaction was heated to 35° C. for 14 h. The resulting slurry wasfiltered through Celite™, and the Celite™ was washed with EtOAc (20 mL).Then EtOAc (40 mL) and water (50 mL) were added to the filtrate. Theaqueous layer was separated, and extracted once with EtOAc (20 mL). Thecombined organic layer was washed with water (50 mL) and brine (20 mL),and concentrated to give a crude oil, which was purified via ISCO silicacolumn (40 g, diluted with 0-30% Hexanes/EtOAc) to give the titleproduct.

Step 4: (2S,3R)-methyl3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylpropanoate

Bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (1.0 g) and(S)-1-[(R)-2-(Di-tert-butylphosphino) ferrocenyl]ethyldiphenylphosphine(Josiphos SL-J502-2, CAS#223121-01-5, 1.86 g) were added to DCM (12 mL)and agitated for 20 min at rt. Then tetrafluoroboric acid-diethyl ethercomplex (1.0 g) was added slowly and stirred for 20 min at rt. Thereaction mixture was diluted with DCM (100 mL) and added to a catalystbomb with a MeOH rinse. Then (Z)-methyl3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylacrylate (2.57 g, 7.97mmol) was added to the catalyst bomb with MeOH (200 mL) and agitated todissolve. The catalyst bomb was pressurized to 500 psi with hydrogen,then heated to 80° C. and shaken for 20 h. Then the reaction was cooled,filtered through Celite™ and washed with MeOH. The filtrate wasconcentrated to give the crude product.

Step 5: (2S,3R)-methyl3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropanoate

To a solution of (2S,3S)-methyl3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylpropanoate (4.81 g, 13mmol) in methanol (67 ml) in a 25 ml glass shaker vessel, was 8% Pd-2%Pt/C (1.5 g, 35 wt % loading, 50 w/w, Johnson Matthey lot# F27N23). Thenthe vessel was evacuated and purged with nitrogen three times, andcharged with 50 psi of hydrogen gas. The reaction was heated to 25° C.for 6 h, then filtered through Celite™, which was washed with MeOH (50mL). The filtrate is concentrated to give the title compound.

Intermediate 2 (2S,3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate

A solution of (2S,3R)-methyl3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropanoate (1 g, 4.27 mmol) inDCM (10 mL) was cooled to 0° C., then NIS (0.960 g, 4.27 mmol) was addedslowly over several minutes. After 2 h, the reaction was poured intosaturated Na₂SO₃ (aq, 50 mL). The organic layer was separated, driedover Na₂SO₄ and concentrated. The resulting residue was purified by HPLC(ISCO 120 g, 0 to 50% EtOAc/Hex) to give the title compound. ¹H NMR (500MHz, CDCl₃) δ7.60 (d, 1H), 6.85 (s, 1H), 6.50 (d, 1H), 5.30 (br, 1H),3.75 (s, 3H), 2.80 (m, 1H), 1.90 (t, 1H), 1.05 (m, 1H), 0.97 (d, 3H),0.60 (m, 1H), 0.37 (m, 1H), 0.27 (m, 1H), 0.01 (m, 1H). (m/z): 361.07(M+H)⁺.

Intermediate 3 Methyl(2S,3R)-3-cyclobutyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate

Step A: cyclobutyl(1H-imidazol-1-yl)methanone To a solution ofcyclobutanecarboxylic acid (257 g, 2.57 mol) in THF (2600 mL) was addedCDI (500 g, 3.08 mol) in portions at 10° C. After the addition, themixture was stirred at 10° C. for 1 hr. Then the mixture wasconcentrated to afford cyclobutyl(1H-imidazol-1-yl)methanone, which wasused in the next step.

Step B: 3-ethoxy-2-methyl-3-oxopropanoic acid A suspension of diethyl2-methylmalonate (500.00 g, 2.87 mol, 1.00 eq) and KOH (177.16 g, 3.16mol, 1.10 eq) in EtOH (5000 mL) was stirred at 70° C. for 12 hr. Thereaction mixture was concentrated under vacuum. The resulting residuewas diluted with water and the aqueous layer was extracted with EtOAc.The organic layer was separated, dried and concentrated to provide3-ethoxy-2-methyl-3-oxopropanoic acid.

Step C: ethyl 3-cyclobutyl-2-methyl-3-oxopropanoate A suspension of3-ethoxy-2-methyl-3-oxopropanoic acid (400 g, 2.74 mol) and Mg(C₂H₅O)₂(313 g, 2.74 mol) in THF (4000 mL) was stirred at 70° C. for 12 hr.After the cooling down to 10° C., cyclobutyl(1H-imidazol-1-yl)methanone(702 g, crude) was added and the mixture was heated at reflux for 20 h.Then the mixture was filtered and the filtrate was concentrated. Theresulting residue was diluted with DCM, washed with water and brine,dried and concentrated. The resulting residue was purified by silica gelchromatography to afford ethyl 3-cyclobutyl-2-methyl-3-oxopropanoate.

Step D: methyl 3-cyclobutyl-2-methyl-3-oxopropanoate A suspension ofethyl 3-cyclobutyl-2-methyl-3-oxopropanoate (321 g, 1.74 mol, 1.00 eq)and NaOMe (97.6 g, 1.74 mol, 1.00 eq) in MeOH (3200 mL) was stirred at60° C. overnight. The mixture was concentrated and the resulting residuewas diluted with DCM and water. The organic layer was separated andconcentrated to provide a crude residue, which was purified by silicagel column chromatography to afford methyl3-cyclobutyl-2-methyl-3-oxopropanoate.

Step E:3-cyclobutyl-2-methyl-3-[[(4-methylbenzene)sulfonyl]oxy]prop-2-enoate Toa solution of methyl 3-cyclobutyl-2-methyl-3-oxopropanoate (170.00 g,998.79 mmol, 1.00 eq) in THF (2550 mL) at rt, NaHMDS (219.78 g, 1.20mol, 1.20 Eq) was added drop wise. After the addition, the mixture wasstirred at 0° C. for 30 min. Solid p-tolylsulfonyl4-methylbenzenesulfonate (358.59 g, 1.10 mol) was added in portions at0° C. and the mixture was stirred at 0° C. for 1 hr. The mixture wasthen poured into ice-water and extracted with DCM. The organic layer wasseparated, washed with brine and concentrated. The resulting residue waspurified by silica gel column chromatography to afford3-cyclobutyl-2-methyl-3-[[(4-methylbenzene)sulfonyl]oxy]prop-2-enoate.

Step G: methyl (Z)-3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylacrylate Toa 5 L, 4-necked round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, were added a solution of methyl3-cyclobutyl-2-methyl-3-[[(4-methylbenzene)sulfonyl]oxy]prop-2-enoate(295 g, 909.39 mmol, 1.00 eq) in 1,4-dioxane (2950 mL),3-hydroxyphenylboronic acid (124.7 g, 904.09 mmol, 1.00 eq), 2Npotassium carbonate (1357 mL, 3.00 equiv) and Pd(PPh₃)₄(52.6 g, 45.52mmol, 0.05 equiv). The resulting solution was stirred for 1 h at 80° C.in an oil bath. Then the solids were filtered off, and the resultingfiltrate was extracted with 3×800 mL of ethyl acetate. The organiclayers combined, washed with 1×1000 mL of saturated aqueous NH₄Cl, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue purified by silica gel chromatography (solvent: ethylacetate/petroleum ether (1:2)) to afford (Z)-methyl3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylacrylate.

Step H: methyl(2S,3R)-3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylpropanoate To a roundbottomed flask, evacuated and purged with nitrogen three times, wasadded bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium (II) (2.2 g, 6.89mmol), followed by(R)-1-[(SP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(3.96 g, 7.29 mmol). Methanol (300 mL) was added to the flask and themixture was stirred between 20 and 30° C. for 30 min under nitrogen.

Then tetrafluoroboric acid-diethylether complex (2.231 g, 13.78 mmol)was added dropwise to the mixture over a period of 10-20 min. Theresulting mixture was stirred at 20 to 30° C. for 1 h under nitrogen. Aseparate flask was charged with (Z)-methyl3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylacrylate (100 g, 405 mmol).Methanol (500 mL) was added to this flask and argon was bubbled throughthe solution for 1 h to 2 h. To this solution was added, under argon,the ruthenium catalyst solution prepared in the first flask.

The resulting solution was evacuated and purged with argon three times,and was then evacuated and filled with hydrogen six times. The reactionmixture was then stirred at 80° C. for 19 h under hydrogen atmosphere(3.5 to 4.0 MPa).

The reaction mixture was cooled to between 20 and 30° C. and filteredthrough 50 g diatomite. The filtrate was concentrated to approximately1-2 vol (milliliters solvent per grams of starting material). To thiscrude mixture was added MTBE (500 mL) and the mixture was concentratedagain to approximately 1-2 vol. To this crude mixture was added MTBE(1000 mL) and the mixture was treated with decolorizing carbonovernight, filtered through 50 g diatomite then concentrated toapproximately 1-2 vol. Then toluene (100 mL) was added to the solution,which was kept at a temperature between 25 and 30° C. Then heptane (600mL) was added and the mixture was cooled to 15° C. and stirred for 3 to6 hours. The resulting solid was collected via filtration and dried at50-60° C. for 17 h to afford methyl(2S,3R)-3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylpropanoate.

Step I: Methyl(2S,3R)-3-cyclobutyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoateMethyl(2S,3R)-3-cyclobutyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate wasprepared using a method similar to that outlined in the preparation ofIntermediate 2 and starting from methyl(2S,3R)-3-cyclobutyl-3-(3-hydroxyphenyl)-2-methylpropanoate.

Scheme 2 provides a route to prepare the compounds of the presentinvention. Suzuki cross-coupling of boronic acid 1 and aldehyde 2,followed by allyl Grignard addition to aldehyde 3 delivered thehomoallylic alcohol 4. Heck reaction of aryl iodide 5 with homoallylicalcohol 4 gave diol 6. Reduction of the alkene was achieved viapalladium-mediated hydrogenation to give 7. An intramolecular Mitsonobureaction resulted in ring closure to deliver the tetrahydrobenzoxapinering 8. SFC separation of the benzylic diastereomers was followed byhydrolysis of the methyl ester to give the final compound 10.

Scheme 3 provides an alternative route to prepare the compounds of thepresent invention. Suzuki cross-coupling of boronic acid 1 and aldehyde2, followed by allyl Grignard addition to aldehyde 3 delivered thehomoallylic alcohol 4. Mitsonobu coupling of the homoallylic alcohol 4and 4-bromo-2-vinylphenol gave the aryl benzyl ether 5. Aryl benzylether 5 was subjected to ring-closing metathesis with catalyticHoveyda-Grubbs 2 reagent to prepare dihyrdobenzoxapiene 6. The propanoicacid moiety was installed using a two step sequence consisting ofNegishi reaction with (3-ethoxy-3-oxopropyl)zinc (II) bromide followedby lithium hydroxide-mediated hydrolysis of the ethyl ester to give acid8. Finally, reduction of the dihydrobenzoxapiene double bond of 8 wasachieved with hydrogenation in the presence of Pd(OH)₂ to providecompound 9.

EXAMPLE 1 (2S,3R)-3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid

Step A: 1-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl) but-3-en-1-ol To asolution of 2-fluoro-4-(2-methoxypyridin-4-yl)benzaldehyde (1.00 g, 4.32mmol) in THF (10 mL) was added allylmagnesium bromide (8.65 mL, 8.65mmol, 1.0 M) dropwise at 0° C. under a N₂ atmosphere. The reactionmixture was stirred at 0° C. for 30 min, and at 20° C. for 3 hours. Thenthe reaction mixture was quenched with saturated NH₄Cl solution (20 mL)and extracted with EtOAc (10 mL×3). The combined organic layers werewashed with brine (30 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to give a residue, which was purifiedby preparative TLC (PE:EtOAc=5:1, v/v) to afford the title compound. ¹HNMR (400 MHz, CDCl₃): δ=8.23 (d, J=5.2 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H),7.44 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.09 (d, J=4.4 Hz, 1H),6.93 (s, 1H), 5.89-5.82 (m, 1H), 5.23-5.19 (m, 2H), 5.13-5.11 (m, 1H),3.99 (s, 3H), 2.63-2.49 (m, 2H).

Step B: (2S, 3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate To asolution of 1-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)but-3-en-1-ol(804 mg, 2.94 mmol) and (2S, 3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate (530 mg,1.47 mmol) in toluene (10 mL) were addedN-cyclohexyl-N-methylcyclohexanamine (575 mg, 2.94 mmol) and t-buxphosPd G1 (CAS#1142811-12-8, 101 mg, 0.147 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at 100° C. for 2 hours, then cooled to roomtemperature and concentrated in vacuo to give a residue, which waspurified by silica gel chromatography (eluted from PE:EtOAc=100:1 to5:1, v/v) to afford the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.22(d, J=5.2 Hz, 1H), 7.65-7.61 (m, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.32-7.29(m, 1H), 7.26-7.25 (m, 1H), 7.08 (d, J=5.6 Hz, 1H), 6.94 (s, 1H),6.73-6.69 (m, 2H), 6.61 (s, 1H), 6.24-6.16 (m, 1H), 5.21-5.18 (m, 1H),3.99 (s, 3H), 3.73 (s, 3H), 2.80-2.66 (m, 3H), 2.32-2.26 (m, 1H),1.88-1.83 (m, 1H), 1.08-1.07 (m, 1H), 0.84 (d, J=4.0 Hz, 3H), 0.57-0.55(m, 1H), 0.36-0.30 (m, 1H), 0.25-0.22 (m, 1H), 0.01-0.03 (m, 1H).

Step C: (2S, 3R)-methyl3-cyclopropyl-3-(4-(4-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate To asolution of (2S, 3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate (610mg, 1.21 mmol) in MeOH (10 mL) was added Pd(OH)₂/C (85.0 mg, 20%). Thereaction mixture was stirred for at 20° C. for 3 hours under H₂ balloonpressure. Then the reaction mixture was filtered, and the filtrate wasconcentrated in vacuo to give the title compound, which was used in thenext step. ¹H NMR (400 MHz, CDCl₃): δ=8.20 (d, J=6.0 Hz, 1H), 7.58 (t,J=7.6 Hz, 1H), 7.41 (dd, J₁₃=8.0 Hz, J₁₂=2.0 Hz, 1H), 7.28 (dd, J₁₃=11.2Hz, J₁₂=2.0 Hz, 1H), 7.07 (dd, J₁₃=7.2 Hz, J₁₂=1.6 Hz, 1H), 7.01 (d,J=8.0 Hz, 1H), 6.92 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 5.17(t, J=6.0 Hz, 1H), 3.99 (s, 3H), 3.72 (s, 3H), 2.80-2.65 (m, 3H),1.88-1.74 (m, 6H), 1.05-0.97 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.56-0.51(m, 1H), 0.34-0.20 (m, 2H), 0.02-0.02 (m, 1H).

Step D: (2S, 3R)-methyl3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl) phenyl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate To a solution of(2S,3R)-methyl 3-cyclopropyl-3-(4-(4-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate (400 mg,0.788 mmol) and triphenylphosphine (289 mg, 1.10 mmol) in DCM (3.0 mL)was added dropwise a solution of diisopropyl azodicarboxylate (0.215 mL,1.10 mmol) in DCM (1.0 mL) at 0° C. under a N₂ atmosphere. The reactionmixture was stirred at 20° C. for 2 hours, then concentrated in vacuo togive a residue, which was purified by preparative TLC (PE:EtOAc=5:1,v/v) to afford the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.25 (d,J=5.2 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.41 (dd, J₁₃=8.4 Hz, J₁₂=2.0 Hz,1H), 7.33-7.30 (m, 1H), 7.11-7.09 (m, 2H), 6.96 (s, 1H), 6.84-6.79 (m,2H), 4.96-4.92 (m, 1H), 4.00 (s, 3H), 3.71 (s, 3H), 3.00 (t, J=12.8 Hz,1H), 2.83-2.76 (m, 2H), 2.24-2.21 (m, 1H), 2.15-2.09 (m, 2H), 1.87 (t,J=10.0 Hz, 1H), 1.72-1.69 (m, 1H), 1.06-0.99 (m, 1H), 0.94 (dd, J₁₃=6.8Hz, J₁₂=5.6 Hz, 3H), 0.57-0.50 (m, 1H), 0.36-0.29 (m, 1H), 0.25-0.19 (m,1H), 0.04-0.04 (m, 1H).

Step E: (2S, 3R)-methyl 3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Peak 1, faster eluting); and (2S, 3R)-methyl 3-cyclopropyl-3-((S orR)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Peak 2, slower eluting)

(2S, 3R)-methyl3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(200 mg, 0.409 mmol) was separated via SFC (using SFC conditions:“Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: ethanol(0.05% DEA) in CO₂ from 5% to 40% Flow rate: 4 mL/min Wavelength: 220nm”) to give (2S, 3R)-methyl 3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methyl-propanoate(Peak 1, faster eluting), and (2S, 3R)-methyl 3-cyclopropyl-3-((S orR)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methyl-propanoate(Peak 2, slower eluting).

Step F: (2S,3R)-methyl 3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid To a solution of (2S, 3R)-methyl 3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methyl-propanoate(Peak 1, faster eluting, 100 mg, 0.204 mmol) in THF/MeOH/H₂O (1.0 mL/1.0mL/1.0 mL) was added LiOH (48.9 mg, 2.04 mmol). The reaction mixture wasstirred at 50° C. for 16 hours, and then cooled to room temperature. Thereaction mixture was then acidified with HCl (1.0 N) to adjust the pH to2, and was extracted with EtOAc (5.0 mL×3). The combined organic layerswere concentrated in vacuo to afford a residue, which was purified bypreparative HPLC (on a GILSON 281 instrument fitted with a PhenomenexGemini C₁₈ (250*21.2 mm*5 um) using water and acetonitrile as theeluents. Mobile phase A: water (neutral), mobile phase B: acetonitrile.Gradient: 33-63% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min) togive (2S,3R)-3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid. ¹H NMR (400 MHz, CDCl₃): δ=8.25 (d, J=4.8 Hz, 1H), 7.79 (t, J=8.0Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.30 (d, J=11.2 Hz, 1H), 7.12-7.10 (m,2H), 6.96 (s, 1H), 6.84-6.83 (m, 2H), 4.92 (d, J=10.0 Hz, 1H), 4.00 (s,3H), 3.00 (t, J=13.2 Hz, 1H), 2.83-2.79 (m, 2H), 2.24-2.09 (m, 3H), 1.94(t, J=10.0 Hz, 1H), 1.75-1.66 (m, 1H), 1.10-1.08 (m, 1H), 0.98 (d, J=6.8Hz, 3H), 0.61-0.60 (m, 1H), 0.36-0.33 (m, 2H), 0.03-0.02 (m, 1H).

To a solution of (2S,3R)-3-cyclopropyl-3-((R orS)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid in MeCN (1.0 mL) and water (1.0 mL) was added aq. NaOH (1.0 eq, 0.5M). The mixture was stirred at 20° C. for 1 hour. Then the reactionmixture was lyophilized to give the sodium salt of the title compound.

TABLE 1 Example 2 was prepared from (2S, 3R)-methyl-3-cyclopropyl-3-((Sor R)-2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methyl-propanoate(Peak 2, slower eluting isomer) in a similar manner to Example 1. LC/MS(ESI) observed Example Structure MW Compound Name [M + 1]+ 2

475.55 (2S,3R)-3-cyclopropyl-3- ((R or S)-2-(2-fluoro-4-(2-methoxypyridin-4- yl)phenyl)-2,3,4,5- tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoic acid 476.2 *stereoisomer at this position

EXAMPLES 3 and 4 (2S, 3R)-3-((R or S)-2-(1-(2, 5-bis (trifluoromethyl)benzyl) azetidin-3-yl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoic acid(Example 3: peak 1, faster eluting isomer), and (2S, 3R)-3-((R orS)-2-(1-(2, 5-bis (trifluoromethyl) benzyl) azetidin-3-yl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoic acid(Example 4: peak 2, slower eluting isomer)

Step A: tert-butyl 3-(1-hydroxybut-3-en-1-yl) azetidine-1-carboxylate

To a solution of tert-butyl 3-formylazetidine-1-carboxylate (2.00 g,10.8 mmol) in THF (20 mL) was added dropwise allylmagnesium bromide(21.6 mL, 21.6 mmol) at 0° C. under a N₂ atmosphere. The reactionmixture was stirred for 30 min at 0° C. and 3 hours at 20° C. (roomtemperature). Then the reaction mixture was quenched with saturatedNH₄Cl (20 mL) and extracted with EtOAc (10 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to give the titlecompound, which was used in the next step. ¹H NMR (400 MHz, CDCl₃):δ=5.85-5.75 (m, 1H), 5.19-5.04 (m, 2H), 4.14-3.71 (m, 6H), 2.24-2.04 (m,2H), 1.44 (s, 9H).

Step B: tert-butyl 3-(4-(4-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2-hydroxyphenyl)butanoyl) azetidine-1-carboxylate To a solution of tert-butyl3-(1-hydroxybut-3-en-1-yl)azetidine-1-carboxylate (2.27 g, 9.99 mmol) inDMF (20 ml) were added lithium chloride (1.05 g, 24.9 mmol), lithiumacetate (1.65 g, 24.9 mmol), (2S,3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methyl propanoate (3.00 g,8.33 mmol), tetrabutylammonium chloride (4.63 g, 16.6 mmol) and PdOAc₂(0.374 g, 1.66 mmol) under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at 100° C., then diluted with water (20 mL). Themixture was extracted with EtOAc (30 mL×3). The combined organic layerswere washed with water (100 mL) twice. Then the organic layer wasconcentrated in vacuo to give crude product, which was purified viasilica gel column (PE:EtOAc=20:1) to give the title compound. MS (ESI)m/z: 482.2 [M+Na⁺].

Step C: tert-butyl 3-(4-(4-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2-hydroxyphenyl)-1-hydroxybutyl)azetidine-1-carboxylate A mixture of compound tert-butyl 3-((E)-4-(4-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2-hydroxyphenyl)-1-hydroxybut-3-en-1-yl)azetidine-1-carboxylate (100 mg, 0.218 mmol) and PdOH₂/C (1.528 mg, 20%)in MeOH (10 ml) was stirred at 15° C. for 16 hours under H₂ atmosphere.The mixture was filtered, and the filtrate was dried over MgSO₄ andconcentrated in vacuo to give the crude product. The crude product waspurified by prep-TLC (PE:EtOAc=3:1) to give the title compound. MS (ESI)m/z: 462.3 [M+H⁺].

Step D: tert-butyl 3-(8-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-2-yl) azetidine-1-carboxylate To a solutiontert-butyl 3-(4-(4-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2-hydroxyphenyl)-1-hydroxybutyl)azetidine-1-carboxylate (453 mg, 0.981 mmol) and triphenylphosphine (515mg, 1.96 mmol) in DCM (8.0 mL) was added a solution of (E)-diisopropyldiazene-1,2-dicarboxylate (397 mg, 1.96 mmol) in DCM (2.0 mL) at 0° C.under N₂ atmosphere. The reaction mixture was stirred for 1 hour at 20°C., then concentrated in vacuo to give a residue, which was purified byprep-TLC(PE:EtOAc=5:1) to give the title compound.

Step E: (2S, 3R)-methyl 3-(2-(azetidin-3-yl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoate To asolution of tert-butyl3-(8-(1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-2-yl) azetidine-1-carboxylate (60.0 mg, 0.135mmol) in DCM (10 ml) was added 2, 2, 2-trifluoroacetic acid (308 mg,2.71 mmol). Then the mixture was stirred at 20° C. for 30 min, andconcentrated in vacuo to give the title compound, which was used in nextstep. MS (ESI) m/z: 344.1 [M+H⁺].

Step F: (2S, 3R)-methyl 3-(2-(1-(2, 5-bis (trifluoromethyl) benzyl)azetidin-3-yl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoate Amixture of compound K₂CO₃ (66.0 mg, 0.477 mmol), 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (110 mg, 0.358 mmol) and methyl3-(2-(azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoate(41.0 mg, 0.119 mmol) in MeCN (10 ml) was stirred at 20° C. for 10hours. Then water (10 mL) was added, and the reaction mixture wasextracted with DCM (5 ml) twice. The combined organic layers were driedover Na₂SO₄, and concentrated in vacuo to give the crude product. Thecrude product was purified via prep-TLC (PE:EtOAc=5:1) to give the titlecompound. MS (ESI) m/z: 570.2 [M+H⁺].

Step G: (2S, 3R)-3-(2-(1-(2, 5-bis (trifluoromethyl) benzyl)azetidin-3-yl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoic acid Amixture of LiOH (17.24 mg, 0.720 mmol) and (2S,3R)-methyl3-(2-(1-(2,5-bis(trifluoromethyl)benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoate(41 mg, 0.072 mmol) in water (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL)was stirred at 50° C. for 2 hours. The reaction mixture was thenacidified with HCl (2N, 1.0 mL) and diluted with DCM (10 mL). Then thereaction mixture was washed with water (20 ml). The organic layer wasseparated, dried over anhydrous MgSO₄ and filtered. The filtrate wasconcentrated to give the crude product, which was purified by prep-HPLC(on a GILSON 281 instrument fitted with a Phenomenex Synergi C18100*21.2 mm*4 um using water and acetonitrile as the eluents. Mobilephase A: water (containing 0.1% TFA, v/v), mobile phase B: acetonitrile.Gradient: 32-58% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min) togive the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.15 (s, 1H),7.93-7.80 (m, 2H), 7.10 (d, J=6.4 Hz, 2H), 6.87-6.78 (m, 2H), 4.74-4.58(m, 4H), 4.12 (s, 2H), 3.65 (s, 1H), 3.22 (s, 1H), 2.87-2.76 (m, 3H),2.00 (s, 2H), 1.81-1.78 (m, 1H), 1.61-1.51 (m, 2H), 1.01-1.00 (m, 4H),0.63-0.62 (m, 1H), 0.38-0.37 (m, 2H), 0.05-0.04 (m, 1H).

Step H: (2S, 3R)-3-((R orS)-2-(1-(2,5-bis(trifluoromethyl)benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid and (2S, 3R)-3-((R orS)-2-(1-(2,5-bis(trifluoromethyl)benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid

(2S,3R)-3-(2-(1-(2,5-bis(trifluoromethyl)benzyl)azetidin-3-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid and (25 mg, 0.045 mmol) was separated via SFC (SFC conditions:Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd, column: AD(250*30 mm 5 um), mobile phase: 10% EtOH+NH₃H₂O 50 mL/min; wavelength:220 nm) to give 2 peaks: peak 1 (faster eluting isomer; Example 3):(2S,3R)-3-((R orS)-2-(1-(2,5-bis(trifluoromethyl)benzyl)-azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid, and peak 2 (slower eluting isomer; Example 4): (2S,3R)-3-((R orS)-2-(1-(2,5-bis(trifluoromethyl)-benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid. To the faster eluting isomer (Example 3) (2S,3R)-3-((R orS)-2-(1-(2,5-bis(trifluoromethyl)-benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid (9 mg, 0.016 mmol) was added a solution of NaOH (aq. 33 mg, 0.5 M)in MeCN (0.5 mL). The mixture was stirred for 1 hour at roomtemperature. Then the reaction mixture was lyophilized to give thesodium salt of Example 3. ¹H NMR (400 MHz, CDCl₃): δ=8.00 (s, 1H), 7.77(d, J=7.2 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.06 (d, J=6.8 Hz, 1H), 6.84(d, J=6.8 Hz, 1H), 3.96 (s, 2H), 3.74-3.64 (m, 3H), 3.40-3.39 (m, 1H),3.13-3.13 (m, 1H), 2.84-2.73 (m, 4H), 2.05-1.99 (m, 2H), 1.86-1.83 (m,1H), 1.64-1.50 (m, 2H), 1.16-1.15 (m, 1H), 1.00 (d, J=5.6 Hz, 3H),0.61-0.60 (m, 1H), 0.38-0.37 (m, 2H), 0.06-0.05 (m, 1H).

To a solution of the slower eluting isomer (Example 4) (2S,3R)-3-((R orS)-2-(1-(2,5-bis(trifluoro-methyl)benzyl)azetidin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-3-cyclopropyl-2-methylpropanoicacid (10 mg, 0.017 mmol) in MeCN (0.5 mL) was added the solution of NaOH(aq. 37 mg, 0.5 M). The mixture was stirred for 1 hour at roomtemperature. Then the reaction mixture was lyophilized to give thesodium salt of Example 4. MS (ESI) m/z: 556.1 [M+H]⁺.

TABLE 2 Example 4 was prepared as described above LC/MS (ESI) observedExample Structure MW Compound Name [M + 1]+ 4

555.55 (2S,3R)-3-((R or S)-2-(1- (2,5-bis(trifluoromethyl)-benzyl)azetidin-3-yl)- 2,3,4,5-tetrahydrobenzo[b]-oxepin-8-yl)-3-cyclopropyl- 2-methylpropanoic acid 556.1 *stereoisomerat this position

EXAMPLE 5(2S,3R)-3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid

Step A: 4-(5-fluoro-2-methoxypyridin-4-yl)benzaldehyde To a solution ofcompounds (5-fluoro-2-methoxypyridin-4-yl)boronic acid (800 mg, 4.68mmol) and 4-bromobenzaldehyde (1.03 g, 5.62 mmol) in THF (10 mL) andwater (2.0 mL) were added K₂CO₃ (1.93 g, 14.0 mmol) and PdCl₂(dppf) (342mg, 0.468 mmol) under a N₂ atmosphere. The reaction mixture was stirredat 100° C. for 2 hours, then water (10 mL) was added and the mixture wasextracted with EtOAc (2 mL×3). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to give a residue, which was purifiedby preparative TLC (PE/EtOAc=5:1) to give the title compound. ¹H NMR(400 MHz, CDCl₃): δ=10.1 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=8.0 Hz, 2H),7.77 (d, J=7.2 Hz, 2H), 6.85 (d, J=5.2 Hz, 1H), 3.97 (s, 3H). MS(ESI)m/z: 232.0 [M+H]⁺.

Step B: 1-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)but-3-en-1-ol To asolution of 4-(5-fluoro-2-methoxypyridin-4-yl)benzaldehyde (650 mg, 2.81mmol) in THF (10 mL) was added allylmagnesium bromide (11.2 mL, 11.2mmol) dropwise at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 30 mins at 0° C., and 3 hours at room temperature. Then thereaction was quenched with saturated NH₄Cl (20 mL) and extracted withEtOAc (5.0 mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to give a residue, which was purified bypreparative TLC (PE:EtOAc=5:1, v/v) to afford the title compound. ¹H NMR(400 MHz, CDCl₃): δ=8.07 (s, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.50 (d, J=7.6Hz, 1H), 6.85 (m, 1H), 5.88-5.80 (m, 1H), 6.93 (s, 1H), 5.24 (t, J=10.4Hz, 2H), 4.83 (d, J=7.6 Hz, 1H), 3.97 (s, 3H), 2.61 (m, 2H). MS(ESI)m/z: 274.1 [M+H]⁺.

Step C:(2S,3R)-methyl-3-cyclopropyl-3-(4-((Z)-4-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoateTo a solution of1-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)but-3-en-1-ol (620 mg, 2.27mmol) and (2S, 3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate (545 mg,1.51 mmol) in toluene (10 mL) were addedN-cyclohexyl-N-methylcyclohexanamine (443 mg, 2.27 mmol) andt-buxhos-palladacycle (104 mg, 0.151 mmol) under a N₂ atmosphere. Thereaction mixture was stirred for 2 hours at 100° C., then cooled to roomtemperature and concentrated in vacuo to give a residue. The residue waspurified via silica gel chromatography (eluted from PE:EtOAc=100:1 to5:1, v/v) to afford the title compound. MS(ESI) m/z: 506.2 [M+H]⁺.

Step D: (2S, 3R)-methyl3-cyclopropyl-3-(4-(4-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate To asolution of (2S, 3R)-methyl (2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate(450 mg, 0.890 mmol) in MeOH (10 mL) was added Pd(OH)₂/C (13.0 mg,0.0890 mmol, 20%). The reaction mixture was stirred for 3 hours at roomtemperature under a H₂ balloon. Then the reaction mixture was filtered,and the filtrate was concentrated in vacuo to give the title compound,which was used in the next step. ¹H NMR (400 MHz, CDCl₃): δ=8.05 (s,1H), 7.57 (d, J=7.6 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.03 (d, J=7.2 Hz,1H), 6.81 (d, J=5.2 Hz, 1H), 6.65-6.61 (m, 2H), 4.86 (d, J=6.8 Hz, 1H),3.94 (s, 3H), 3.74 (s, 3H), 2.80-2.72 (m, 3H), 1.86-1.72 (m, 4H),1.03-0.93 (m, 4H), 0.54 (s, 1H), 0.32-0.21 (m, 2H), 0.01-0.004 (m, 1H).MS(ESI) m/z: 508.2 [M+H]⁺.

Step E: (2S,3R)-methyl3-cyclopropyl-3-(2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a solution of (2S,3R)-methyl3-cyclopropyl-3-(4-(4-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate(345 mg, 0.680 mmol) and triphenylphosphine (357 mg, 1.36 mmol) in DCM(3.0 mL) was added dropwise a solution of DIAD (275 mg, 1.36 mmol) inDCM (1.0 mL) at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at room temperature, then concentrated in vacuo togive a residue, which was purified by preparative TLC (PE:EtOAc=5:1,v/v) to afford the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.09 (s,1H), 7.65-7.58 (m, 4H), 7.12 (d, J=7.2 Hz, 1H), 6.86-6.79 (m, 3H), 4.68(t, J=5.6 Hz, 1H), 3.97 (s, 3H), 3.72 (s, 3H), 3.00 (t, J=13.2 Hz, 1H),2.82-2.78 (m, 2H), 2.22-2.12 (m, 4H), 1.87 (t, J=10.0 Hz, 1H), 1.72-1.62(m, 1H), 1.04 (d, J=4.8 Hz, 1H), 0.94 (t, J=5.6 Hz, 3H), 0.55 (d, J=3.6Hz, 1H), 0.34 (d, J=4.0 Hz, 1H), 0.23 (d, J=4.4 Hz, 1H), 0.12 (s, 1H);MS(ESI) m/z: 490.3[M+H]⁺.

Step F: (2S,3R)-methyl3-cyclopropyl-3-(2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate((2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(60 mg, 0.123 mmol) was separated by SFC (SFC conditions: Column:Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: ethanol (0.05% DEA) inCO₂ from 5% to 40% Flow rate: 4 mL/min Wavelength: 220 nm) to give 2peaks: Peak 1 (faster eluting isomer): (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoate;and Peak 2 (slower eluting isomer): (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate.

Step G: sodium (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a solution of Peak 1 (faster eluting isomer) of (2S,3R)-methyl3-cyclopropyl-3-(2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoate(30 mg, 0.0613 mmol) in THF/MeOH/H₂O (1.0 mL/1.0 mL/1.0 mL) was addedLiOH (15.0 mg, 0.613 mmol). The reaction mixture was stirred at 50° C.for 16 hours, then cooled to room temperature, and acidified with HCl (1mol/L) to pH 2. The mixture was extracted with EtOAc (2 mL×3), and thecombined organic layers were concentrated in vacuo to afford a residue.The residue was purified by preparative HPLC (on a GILSON 281 instrumentfitted with a Phenomenex Gemini C₁₈ (250*21.2 mm*5 um) using water andacetonitrile as the eluents. Mobile phase A: water (neutral), mobilephase B: acetonitrile. Gradient: 33-63% B, 0-10 min; 100% B, 10.5-12.5min; 5% B, 13-15 min) to give(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 5).

To a solution of(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 5, 12.6 mg) in MeCN (0.5 mL) was added a solution of NaOH(aq. 172 mg, 0.5 M). The mixture was stirred for 1 hour at roomtemperature, then the reaction mixture was lyophilized to give thesodium salt of(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 5). ¹H NMR (400 MHz, CDCl₃): δ=8.13 (d, J=1.2 Hz, 1H),7.64-7.58 (m, 4H), 7.12 (d, J=7.6 Hz, 1H), 6.88-6.83 (m, 3H), 4.69 (d,J=10.4 Hz, 1H), 3.98 (s, 3H), 2.97 (t, J=12.8 Hz, 1H), 2.82-2.78 (m,2H), 2.21-2.11 (m, 3H), 1.94 (t, J=10.0 Hz, 1H), 1.75-1.66 (m, 1H),1.10-1.08 (m, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.62-0.61 (m, 1H), 0.37-0.32(m, 2H), 0.03-0.02 (m, 1H). MS(ESI) m/z: 476.2 [M+H]⁺.

To a solution of(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (12.6 mg) in MeCN (0.5 mL) was added the solution of NaOH (aq. 172mg, 0.5 M), the mixture was stirred for 1 hour at 20° C. (roomtemperature). Then the reaction mixture was lyophilized to give thesodium salt of(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid.

TABLE 3 Example 6 was prepared in a similar manner to Example 5 usingthe Peak 2, slower eluting isomer of Example 5, Step F as the startingmaterial in Example 5, Step G. LC/MS (ESI) observed Example Structure MWCompound Name [M + 1]+ 6

475.55 (2S,3R)-3-cyclopropyl-3- ((R or S)-2-(4-(5-fluoro-2-methoxypyridin-4- yl)phenyl)-2,3,4,5- tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoic acid 476.2 *stereoisomer at this position

EXAMPLE 7(2S,3R)-3-cyclopropyl-3-((RS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid

Step A: 5′-fluoro-2′-methoxy-[3,4′-bipyridine]-6-carbaldehyde To asolution of compounds (5-fluoro-2-methoxypyridin-4-yl)boronic acid (1.00g, 5.85 mmol) and 5-bromopicolinaldehyde (1.19 g, 6.44 mmol) in THF (10mL) and water (2.0 mL) were added K₂CO₃ (2.42 g, 1.76 mmol) andPdCl₂(dppf) (428 mg, 0.585 mmol) under a N₂ atmosphere. The reactionmixture was stirred at 100° C. for 2 hours, then water (10 mL) was addedand the mixture was extracted with EtOAc (2 mL×3). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to give a residue,which was purified by preparative TLC (PE/EtOAc=5:1, v/v) to give thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ=10.2 (s, 1H), 8.99 (s, 1H),8.17 (m, 3H), 6.88 (d, J=4.8 Hz, 1H), 3.98 (s, 3H). MS (ESI) m/z: 233.0[M+H]⁺.

Step B: 1-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)but-3-en-1-ol To asolution of 5′-fluoro-2′-methoxy-[3,4′-bipyridine]-6- carbaldehyde (950mg, 4.09 mmol) in THF (10 mL) was added allylmagnesium bromide (8.18 mL,8.18 mmol) dropwise at 0° C. under a N₂ atmosphere. The reaction mixturewas stirred for 30 min at 0° C. and 3 hours at room temperature. Thenthe reaction mixture was quenched with saturated NH₄Cl (20 mL) andextracted with EtOAc (5.0 mL×3). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to give a residue, which was purifiedby preparative TLC (PE:EtOAc=5:1, v/v) to give the title compound. ¹HNMR (400 MHz, CDCl₃): δ=8.77 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=4.8 Hz,1H), 7.46 (d, J=4.2 Hz, 1H), 5.91-5.84 (m, 1H), 5.19-5.15 (m, 2H),4.91-4.88 (m, 1H), 3.97 (s, 3H), 2.73-2.69 (m, 1H), 2.58-2.52 (m, 1H).MS(ESI) m/z: 275.1 [M+H]⁺.

Step C: (2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoateTo a solution of1-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)but-3-en-1-ol (320 mg,1.17 mmol) and (2S, 3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methyl-propanoate (280 mg,0.778 mmol) in Toluene (10 mL) were addedN-cyclohexyl-N-methylcyclohexanamine (229 mg, 1.17 mmol) and t-buxhospalladacycle (54.0 mg, 0.0778 mmol) under a N₂ atmosphere. The reactionmixture was stirred for 2 hours at 100° C., then cooled to roomtemperature and concentrated in vacuo to give a residue. The residue waspurified via silica gel chromatography (eluted from PE:EtOAc=100:1 to5:1, v/v) to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.80(s, 1H), 8.12 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H),7.20 (d, J=8.0 Hz, 1H), 6.85 (d, J=5.2 Hz, 1H), 6.68-6.58 (m, 3H),6.18-6.14 (m, 1H), 5.02 (s, 1H), 3.97 (s, 3H), 3.73 (s, 3H), 2.86-2.71(m, 3H), 1.88-1.83 (m, 1H), 1.01 (s, 1H), 0.95 (d, J=6.8 Hz, 3H),0.57-0.55 (m, 1H), 0.33-0.21 (m, 2H), 0.01-0.03 (m, 1H).

Step D: (2S,3R)-methyl3-cyclopropyl-3-(4-(4-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoateTo a solution of (2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate(290 mg, 0.572 mmol) in MeOH (10 mL) was added Pd(OH)₂/C (8.00 mg,0.0572 mmol, 20%). The reaction mixture was stirred for 3 hours at roomtemperature under a H₂ balloon. Then the reaction mixture was filtered,and the filtrate was concentrated in vacuo to give the title compound,which was used in the next step.

Step E: (2S, 3R)-methyl3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl) phenyl)-2, 3, 4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate To a solution of(2S,3R)-methyl3-cyclopropyl-3-(4-(4-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate(225 mg, 0.442 mmol) and triphenylphosphine (232 mg, 0.884 mmol) in DCM(3.0 mL) was added dropwise a solution of DIAD (179 mg, 0.884 mmol) inDCM (1.0 mL) at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at room temperature, then concentrated in vacuo togive a residue, which was purified by preparative TLC (PE:EtOAc=5:1,v/v) to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ=8.78 (s,1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.13 (d, J=6.8Hz, 1H), 6.86 (d, J=5.2 Hz, 1H), 6.82-6.81 (m, 3H), 4.77 (s, 1H), 3.97(s, 3H), 3.71 (s, 3H), 2.84 (t, J=27.8 Hz, 1H), 2.83-2.77 (m, 2H), 2.48(s, 1H), 1.87 (t, J=10.0 Hz, 1H), 1.74-1.70 (m, 1H), 1.03 (s, 1H),0.94-0.92 (m, 3H), 0.54 (s, 1H), 0.33-0.21 (m, 2H), 0.02 (m, 1H).MS(ESI) m/z: 491.3 [M+H]⁺.

Step F: (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate

The (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(190 mg, 0.386 mmol) was separated by SFC (SFC conditions: Column:Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: ethanol (0.05% DEA) inCO₂ from 5% to 40% Flow rate: 4 mL/min Wavelength: 220 nm) to give(2S,3R)-methyl 3-cyclopropyl-3-((R orS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methyl-propanoate(Peak 1, faster eluting isomer); and (2S,3R)-methyl 3-cyclopropyl-3-((RorS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Peak 2, slower eluting isomer).

Step G:(2S,3R)-3-cyclopropyl-3-(2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 7) To a solution of Peak 1 (faster eluting isomer) of(2S,3R)-methyl 3-cyclopropyl-3-((R orS)-2-(5′-fluoro-2′-methoxy-[3,4′-bipyridin]-6-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoate(90.0 mg, 0.184 mmol) in THF/MeOH/H₂O (1.0 mL/1.0 mL/1.0 mL) was addedLiOH (44.0 mg, 1.84 mmol). The reaction mixture was stirred at 50° C.for 16 hours, then cooled to room temperature. The reaction mixture wasacidified with HCl (1 mol/L) to pH 2 and extracted with EtOAc (2 mL×3).The combined organic layers were concentrated in vacuo to afford aresidue, which was purified by preparative HPLC (on a GILSON 281instrument fitted with a Phenomenex Gemini C₁₈ (250*21.2 mm*5 um) usingMobile phase A: water (neutral), mobile phase B: acetonitrile. Gradient:33-63% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min) to give thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ=8.13 (d, J=1.2 Hz, 1H),7.64-7.58 (m, 3H), 7.12 (d, J=7.6 Hz, 1H), 6.88-6.83 (m, 3H), 4.69 (d,J=10.8 Hz, 1H), 3.98 (s, 3H), 2.97 (t, J=12.8 Hz, 1H), 2.82-2.79 (m,2H), 2.21-2.11 (m, 3H), 1.94 (t, J=10.0 Hz, 1H), 1.72-1.69 (m, 1H),1.10-1.08 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.63-0.61 (m, 1H), 0.37-0.32(m, 2H), 0.03-0.02 (m, 1H). MS(ESI) m/z: 477.2 [M+H]⁺.

To a solution of(2S,3R)-3-cyclopropyl-3-(2-(2-fluoro-4-(2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 7, 68.9 mg) in MeCN (0.5 mL) was added a solution of NaOH(aq. 172 mg, 0.5 M). The mixture was stirred for 1 hour at roomtemperature. Then the reaction mixture was lyophilized to give thesodium salt of the title compound.

TABLE 4 Example 8 was prepared in a similar manner to Example 7 usingPeak 2, slower eluting isomer of Example 7 Step F as the startingmaterial for Example 7 Step G. LC/MS (ESI) observed Example Structure MWCompound Name [M + 1]+ 8

476.55 (2S,3R)-3-cyclopropyl- 3-((R or S)-2-(5′-fluoro-2′-methoxy-[3,4′- bipyridin]-6-yl)-2,3,4,5- tetrahydrobenzo[b]oxepin-8-yl)-2- methylpropanoic acid 477.2 *stereoisomer at this position

EXAMPLE 93-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)propanoicacid

Step 1: 2′,6′-dimethyl-[1,1′-biphenyl]-3-carbaldehyde

To a degassed solution of 3-bromobenzaldehyde (500 mg, 2.70 mmol),(2,6-dimethylphenyl)boronic acid (608 mg, 4.05 mmol), and Pd(PPh₃)₄ (156mg, 0.14 mmol) in dioxane (5 mL) was added K₂CO₃ (2N, 4.05 mL, 8.11mmol). The reaction was heated to 100° C. After 16 h, the mixture waspoured into NH₄Cl (sat, 25 mL) and extracted with EtOAc (2×25 mL). Thecombined organic layers were dried over MgSO₄ and concentrated. Theresulting residue was purified by HPLC (ISCO 40 gram silica gelcartridge, 0 to 40% EtOAc/Hex) to give the title compound.

Step 2: 1-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)but-3-en-1-ol

To a solution of 2′,6′-dimethyl-[1,1′-biphenyl]-3-carbaldehyde (850 mg,4.04 mmol) in THF (10 mL) at 0° C. was added allyl Grignard (1M in THF,4.85 mL). After 30 minutes, the reaction was quenched by the slowaddition of 25 mL NH₄C₁ (saturated, aqueous). The mixture was extractedwith EtOAc (2×25 mL). The combined organic layers were dried over MgSO₄and concentrated. The resulting residue was purified by HPLC (40 gramsilica gel ISCO cartridge, 0 to 40% EtOAc/hex) to give the titlecompound.

Step 3:3′-(1-(4-bromo-2-vinylphenoxy)but-3-en-1-yl)-2,6-dimethyl-1,1′-biphenyl

To a solution of 1-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)but-3-en-1-ol(100 mg, 0.396 mmol), 4-bromo-2-vinylphenol (79 mg, 0.396 mmol), andtriphenylphosphine (208 mg, 0.793 mmol) in toluene (4 mL) was slowlyadded DIAD (0.154 mL, 0.793 mmol) dropwise. After 16 h, the reaction wasfiltered and then concentrated. The resulting residue was purified byHPLC (40 gram silica gel ISCO cartridge, 0 to 40% EtOAc/hex) to give thetitle compound.

Step 4:7-bromo-2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepine

To a solution of3′-(1-(4-bromo-2-vinylphenoxy)but-3-en-1-yl)-2,6-dimethyl-1,1′-biphenyl(28 mg, 0.065 mmol) in DCM (6 mL) was added Hoveyda-Grubbs Catalyst2^(nd) Generation (CAS #301224-40-8, 4 mg, 0.006 mmol) and the reactionwas heated to reflux. After 1 hour, the reaction was cooled to roomtemperature, and the volatiles were removed in vacuo. The resultingresidue was purified by HPLC (40 gram silica gel ISCO cartridge, 0 to40% EtOAc/hex) to give the title compound.

Step 5: ethyl3-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepin-7-yl)propanoate

To a degassed solution of7-bromo-2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepine(25 mg, 0.062 mmol) and Sphos Pd G2 (CAS #1028206-58-7, 4.7 mg, 0.006mmol) in THF (3 mL) was added (3-ethoxy-3-oxopropyl)zinc(II) bromide(Rieke Metals, Inc., 0.5 M solution in THF, 0.370 mL, 0.185 mmol). Thereaction was heated to 70° C. in a sealed vial with a teflon screw cap.After 16 h, the reaction was cooled to room temperature and then pouredinto NH₄Cl (saturated, 25 mL). The mixture was extracted with EtOAc(2×25 mL). The combined organic layers were dried over MgSO₄ andconcentrated. The resulting residue was purified by HPLC (40 gram silicagel ISCO cartridge, 0 to 40% EtOAc/hex) to give the title compound.

Step 6:3-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepin-7-yl)propanoicacid

To a slurry of ethyl3-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepin-7-yl)propanoate(17 mg, 0.04 mmol) and THF (1 mL) in LiOH (10 mg, 0.40 mmol) was addedMeOH (1 ml) and water (1 ml). The resulting mixture was heated to 60° C.After 1 hour, the reaction mixture was poured into 1N HCl (10 mL) andextracted with EtOAc (2×10 mL). The combined organic layers were driedover MgSO₄ and concentrated. The resulting residue was purified by HPLC(40 gram silica gel ISCO cartridge, 0 to 100% EtOAc/hex) to give thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (m, 2H), 7.22 (s, 1H),7.18 (m, 1H), 7.15 (m, 3H), 7.03 (s, 1H), 6.99 (m, 2H), 6.40 (d, 1H),6.01 (dd, 1H), 5.00 (d, 1H), 3.05 (dd, 1H), 2.95 t, 2H), 2.81 (dd, 1H),2.70 (t, 2H), 2.07 (s, 6H); (m/z): 381.2 (M-18+H)⁺.

Step 7:3-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)propanoicacid

To a solution of3-(2-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)-2,3-dihydrobenzo[b]oxepin-7-yl)propanoicacid (10 mg, 0.025 mmol) in EtOAc (1 mL) was added Pd(OH)₂ (1 mg, 20 wt%, 0.001 mmol). The mixture was vigorously stirred under a balloon ofhydrogen gas. After 2 hours, the reaction was filtered through Celite™and the filtrate concentrated to give the title compound. ¹H NMR (500MHz, CDCl₃) δ7.48 (br, 2H), 7.21 (s, 1H), 7.10-7.20 (m, 4H), 7.01 (s,1H), 6.98 (s, 2H), 4.62 (d, 1H), 3.00 (t, 1H), 2.92 (t, 2H), 2.78 (dd,1H), 2.70 (t, 2H), 2.24-2.10 (m, 2H), 2.04 (s, 6H), 1.62 (q, 2H); (m/z):383.4 (M-18+H)⁺.

EXAMPLE 10

Sodium (2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Isomer 1)

Step A: (2S,3R)-methyl3-cyclobutyl-3-(4-(4-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoateA solution of (2S,3R)-methyl3-cyclobutyl-3-(4-((E)-4-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate(550 mg, 1.061 mmol; prepared in a manner analogous to that in Example5, Step C, but substituting (2S,3R)-methyl3-cyclobutyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate for (2S,3R)-methyl 3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate)in anhydrous MeOH (27 mL) was transferred to a flask which was flushedwith nitrogen. Then dry Pd/C (113 mg, 0.106 mmol) was added. The flaskwas evacuated and backfilled with hydrogen three times. The reaction wasstirred at 15° C. under 1 atm of hydrogen for 16 hours. Then thecatalyst was filtered off, and the filtrate was concentrated by rotaryevaporator to give (2S,3R)-methyl3-cyclobutyl-3-(4-(4-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate,which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃): δ=7.54 (d, J=7.0 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.08(t, J=9.4 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.94 (dd, J=3.1, 6.3 Hz, 1H),6.87-6.79 (m, 1H), 6.59 (d, J=7.4 Hz, 1H), 6.56-6.52 (m, 1H), 4.91-4.79(m, 1H), 3.83 (s, 3H), 3.68 (s, 3H), 2.79-2.49 (m, 5H), 2.01-1.92 (m,1H), 1.91-1.68 (m, 5H), 1.53-1.45 (m, 1H), 0.89 (d, J=6.8 Hz, 3H)

Step B: (2S,3R)-methyl3-cyclobutyl-3-(2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a flask was added (2S,3R)-methyl3-cyclobutyl-3-(4-(4-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate(426 mg, 0.818 mmol) and triphenylphosphine (300 mg, 1.15 mmol) under anitrogen atmosphere. Then anhydrous DCM (4 mL) was added via syringe,and the colorless solution was cooled to 0° C. A solution of DIAD (0.223ml, 1.14 mmol) in DCM (2 mL) was added dropwise over 1 hour. Thereaction was stirred at 15° C. for 12 hours. Then the reaction mixturewas directly purified by preparative TLC (silica gel, PE:EtOAc=5:1, v/v)to give (2S,3R)-methyl3-cyclobutyl-3-(2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate.¹H NMR (400 MHz, CDCl₃): δ=7.60 (d, J=7.8 Hz, 2H), 7.55 (d, J=7.8 Hz,2H), 7.13-7.03 (m, 2H), 7.01-6.95 (m, 1H), 6.89-6.81 (m, 1H), 6.79-6.76(m, 1H), 6.76-6.72 (m, 1H), 4.67-4.59 (m, 1H), 3.85 (s, 3H), 3.70-3.63(m, 3H), 2.98 (t, J=13.2 Hz, 1H), 2.82-2.72 (m, 2H), 2.65-2.50 (m, 2H),2.27-2.04 (m, 3H), 2.01-1.90 (m, 1H), 1.77-1.56 (m, 6H), 0.89-0.87 (m,3H)

Step C: (2S,3R)-methyl 3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Faster Eluting Isomer) and (2S,3R)-methyl 3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Slower Eluting Isomer) (2 S,3R)-Methyl3-cyclobutyl-3-(2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(310 mg, 0.617 mmol) was separated by SFC (Column: Chrialpak AD (250mm*30 mm, 5 m); Mobile phase: A: Supercritical CO₂, B: MeOH (0.05%NH₃H₂O), A:B=60:40 at 50 mL/min; Column Temp: 38° C.; Nozzle Pressure:100 Bar; Wavelength: 220 nm) to afford (2S,3R)-methyl 3-cyclobutyl-3-((RorS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpro-panoate(Faster Eluting Isomer) and (2S,3R)-methyl 3-cyclobutyl-3-((S orR)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoate(Slower Eluting Isomer).

Step D: Sodium (2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a solution of (2S,3R)-methyl 3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Faster eluting isomer from Step 3; 134 mg, 0.267 mmol) in THF (0.5 mL),MeOH (0.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate(112 mg, 2.67 mmol). The mixture was heated to 50° C. for 12 hours, andthen acidified to pH 3 by adding concentrated aqueous HCl. The solventswere removed by rotary evaporator. The resulting residue was purified bypreparative HPLC (preparative HPLC on a GILSON 281 instrument fittedwith a YMC-Actus Triart C18 150*30 mm*5 m using water and acetonitrileas the eluents. mobile phase A: water (containing 0.1% TFA, v/v), mobilephase B: acetonitrile. Gradient: 52-82% B, 0-10 min; 100% B, 10.5-12.5min; 5% B, 13-15 min) to give (2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Isomer 1).(2S,3R)-3-Cyclobutyl-3-((R)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Isomer 1, 67.2 mg, 0.138 mmol) was dissolved in 1 mL ofacetonitrile. To the solution was added 276 mg of NaOH solution (2%wt/wt). The mixture was stirred at 15° C. for 2 h. The clear solutionwas freeze-dried to give sodium (2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Isomer 1). MS (ESI) m/z: 511.2[M+Na]⁺; ¹H NMR (400 MHz, CDCl₃): δ=7.60(d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.09-7.04 (m, 2H), 6.98-6.97(m, 1H), 6.88-6.81 (m, 1H), 6.81-6.74 (m, 2H), 4.64 (d, J=9.6 Hz, 1H),3.84 (s, 3H), 3.05-2.92 (m, 1H), 2.88-2.73 (m, 2H), 2.70-2.56 (m, 2H),2.28-2.03 (m, 4H), 1.85-1.60 (m, 5H), 1.55-1.44 (m, 1H), 0.93 (d, J=7.2Hz, 3H).

EXAMPLE 11

Sodium (2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Isomer 2) Utilizing a method similar to that outlined in Step 4,Example 10, (2S,3R)-methyl 3-cyclobutyl-3-((S orR)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydro-benzo[b]oxepin-8-yl)-2-methylpropanoate(Slower Eluting Isomer) from Step 3, Example 10 was converted to Sodium(2S,3R)-3-cyclobutyl-3-((R orS)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(Isomer 2). MS (ESI) m/z: 511.2 [M+Na]⁺; ¹H NMR (400 MHz, CDCl₃): δ=7.60(d, J=8.4 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.09-7.07 (m, 2H), 6.98-6.97(m, 1H), 6.88-6.82 (m, 1H), 6.79-6.75 (m, 2H), 4.63 (d, J=10.0 Hz, 1H),3.84 (s, 3H), 2.98-2.81 (m, 1H), 2.79-2.63 (m, 2H), 2.61-2.59 (m, 2H),2.20-2.08 (m, 4H), 1.78-1.65 (m, 5H), 1.51-1.49 (m, 1H), 0.92 (d, J=6.4Hz, 3H). EXAMPLES 12 and 13

(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Faster Eluting Isomer) and(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Slower Eluting Isomer)

Step A: (5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)methanol To asolution of (5-fluoro-2-methoxypyridin-4-yl)boronic acid (2.60 g, 15.2mmol) and (5-chloropyrazin-2-yl)methanol (2.00 g, 13.8 mmol) in THF (10mL) and water (2.0 mL) were added K₃PO₄ (8.80 g, 41.5 mmol) andPdCl₂(dppf) (1.01 g, 1.38 mmol) under a N₂ atmosphere. The reactionmixture was stirred at reflux with a 100° C. bath for 2 hours. Then thereaction mixture was added to water (10 mL) and extracted with EtOAc(2.0 mL×3). The combined organic layers were washed with brine (10 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo to give a residue, which was purified by preparative TLC(PE/EtOAc=5:1) to afford(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)methanol. MS(ESI) m/z:236.0 [M+H]⁺.

Step B: 5-(5-fluoro-2-methoxypyridin-4-yl) pyrazine-2-carbaldehyde To asolution of (5-(5-fluoro-2-methoxypyridin-4-yl) pyrazin-2-yl) methanol(1.56 g, 6.64 mmol) in DCM (20 mL) was added Dess-Martin Periodinane(4.22 g, 9.96 mmol) under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at room temperature, then quenched with saturatedNa₂S₂O₃ (30 mL) and extracted with DCM (10 mL×3). The combined organiclayers were washed with aqueous NaOH (0.2 M, 50 mL), followed by brine(50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to give a residue, which was purified by silicagel chromatography (eluted from PE:EtOAc=100:1 to 20:1, v/v) to afford5-(5-fluoro-2-methoxypyridin-4-yl) pyrazine-2-carbaldehyde. ¹H NMR (400MHz, CDCl₃): δ=10.23 (s, 1H), 9.31 (d, J=6.8 Hz, 2H), 8.22 (d, J=2.0 Hz,1H), 7.49 (d, J=4.8 Hz, 1H), 3.99 (s, 3H). MS(ESI) m/z: 234.0 [M+H]⁺

Step C: 1-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)but-3-en-1-olTo a solution of 4-(5-fluoro-2-methoxypyridin-4-yl)benzaldehyde (900 mg,3.86 mmol) in THF (10 mL) was added allylmagnesium bromide (1M indiethyl ether, 4.63 mL, 4.63 mmol) dropwise at 0° C. under a N₂atmosphere. The reaction mixture was stirred for 30 min at 0° C. and 3hours at room temperature. The reaction mixture was then quenched withsaturated NH₄C₁ (20 mL) and extracted with EtOAc (5.0 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo togive a residue, which was purified by preparative TLC (PE:EtOAc=5:1,v/v) to afford1-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)but-3-en-1-ol. ¹H NMR(400 MHz, CDCl₃): δ=9.08 (s, 1H), 8.81 (s, 1H), 8.17 (d, J=2.4 Hz, 1H),7.43 (s, J=4.8 Hz, 1H), 5.90-5.83 (m, 1H), 5.22-5.18 (m, 2H), 4.98 (s,1H), 3.97 (s, 3H), 3.25 (s, 1H), 2.79-2.73 (m, 1H), 2.63-2.58 (m, 1H).

MS(ESI) m/z: 276.1 [M+H]⁺

Step D: (2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoateTo a solution of1-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)but-3-en-1-ol (532 mg,1.93 mmol) and (2S, 3R)-methyl3-cyclopropyl-3-(3-hydroxy-4-iodophenyl)-2-methylpropanoate (385 mg,1.07 mmol) in toluene (10 mL) were addedN-cyclohexyl-N-methylcyclohexanamine (377 mg, 1.93 mmol) andchloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)-phenyl)]palladium(II)(73.5 mg, 0.107 mmol) under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at 100° C., then cooled to room temperature andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (eluted from PE:EtOAc=100:1 to 5:1, v/v) toafford (2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate.MS(ESI) m/z: 508.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): δ=9.08 (s, 1H), 8.86(s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 6.72-6.62 (m, 3H), 6.23-6.16 (m, 1H), 5.06 (t, J=6.0 Hz, 1H),3.97 (s, 3H), 3.73 (s, 3H), 2.93-2.76 (m, 3H), 2.18 (s, 3H), 1.87-1.82(m, 2H), 1.01-0.93 (m, 4H), 0.56-0.55 (m, 1H), 0.34-0.31 (m, 1H),0.24-0.21 (m, 1H), 0.01-0.03 (m, 1H).

Step E: (2S,3R)-methyl3-cyclopropyl-3-(4-(4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoateTo a solution of ((2S,3R)-methyl3-cyclopropyl-3-(4-((Z)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxybut-1-en-1-yl)-3-hydroxyphenyl)-2-methylpropanoate(510 mg, 1.01 mmol) in MeOH (10 mL) was added Pd(OH)₂/C (14.2 mg, 0.101mmol, 20%). The reaction mixture was stirred for 3 hours at roomtemperature under an H₂ atmosphere (H₂ balloon). The reaction mixturewas then filtered. The filtrate was concentrated in vacuo to give(2S,3R)-methyl3-cyclopropyl-3-(4-(4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxy-butyl)-3-hydroxyphenyl)-2-methylpropanoate,which was used in the next step without further purification. MS(ESI)m/z: 510.2 [M+H]; ¹H NMR (400 MHz, CDCl₃): δ=9.07 (s, 1H), 8.79 (s, 1H),8.17 (d, J=2.4 Hz, 1H), 7.42 (d, J=5.2 Hz, 1H), 7.04 (d, J=7.2 Hz, 2H),6.66-6.62 (m, 2H), 5.94 (m, 1H), 5.04 (s, 1H), 3.97 (s, 3H), 3.73 (s,3H), 3.50 (s, 2H), 2.80-2.86 (m, 4H), 2.04-1.81 (m, 6H), 1.03 (d, J=4.8Hz, 1H), 0.94 (d, J=6.4 Hz, 6H), 0.24-0.20 (m, 2H), 0.02-0.01 (m, 1H).

Step F: (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a solution of (2S,3R)-methyl3-cyclopropyl-3-(4-(4-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-4-hydroxybutyl)-3-hydroxyphenyl)-2-methylpropanoate(495 mg, 0.972 mmol) and triphenylphosphine (509 mg, 1.94 mmol) in DCM(10 mL) was added dropwise a solution of DIAD (392 mg, 1.94 mmol) in DCM(1.0 mL) at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred for 2 hours at room temperature. Then the reaction mixture wasconcentrated in vacuo to give a residue, which was purified by silicagel preparative TLC (PE:EtOAc=5:1, v/v) to afford (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxy-pyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate.MS(ESI) m/z: 492.3 [M+H]; ¹H NMR (400 MHz, CDCl₃): δ=9.15 (s, 1H), 9.07(s, 1H), 8.18 (s, 1H), 7.46 (d, J=4.8 Hz, 1H), 7.14 (d, J=6.0 Hz, 2H),6.89-6.82 (m, 2H), 4.85-4.81 (m, 1H), 3.99 (s, 3H), 3.72 (s, 3H), 3.01(t, J=13.2 Hz, 1H), 2.86-2.76 (m, 1H), 2.53 (d, J=13.2 Hz, 2H),2.18-2.04 (m, 2H), 1.89 (t, J=10.4 Hz, 1H), 1.78 (q, J=12.0 Hz, 1H),1.04-0.93 (m, 4H), 0.56-0.55 (m, 1H), 0.36-0.33 (m, 1H), 0.25-0.22 (m,1H), 0.01-0.01 (m, 1H).

Step G: (2S,3R)-methyl3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoateTo a solution of compound ((2S,3R)-methyl 3-cyclopropyl-3-((R orS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoate(278 mg, 0.566 mmol) in THF/MeOH/H₂O (1.0 mL/1.0 mL/1.0 mL) was addedLiOH (135 mg, 5.66 mmol). The reaction mixture was stirred at 50° C. for16 hours. After the mixture was cooled to room temperature, the reactionmixture was acidified to pH=2 with 1N HCl_((aq.)) and extracted withEtOAc (2.0 mL×3). The combined organic layers were concentrated in vacuoto afford a residue which was purified by preparative HPLC (on a GILSON281 instrument fitted with a Phenomenex Gemini C₁₈ (250*21.2 mm*5 um)using water and acetonitrile as the eluents. Mobile phase A: water(neutral), mobile phase B: acetonitrile. Gradient: 33-63% B, 0-10 min;100% B, 10.5-12.5 min; 5% B, 13-15 min) to give compound(2S,3R)-3-cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid.

Step H:(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 12, Faster Eluting Isomer) and(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 13, Slower Eluting Isomer)(2S,3R)-3-Cyclopropyl-3-((RS)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (248 mg, 0.520 mmol) was subjected to chiral SFC purification(Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: ethanol(0.05% DEA) in CO₂ from 5% to 40% Flow rate: 4 mL/min Wavelength: 220nm) to afford(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxy-pyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methylpropanoicacid (Example 12, Faster Eluting Isomer) and(2S,3R)-3-cyclopropyl-3-((RS)-2-(5-(5-fluoro-2-methoxypyridin-4-yl)pyrazin-2-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-2-methyl-propanoicacid (Example 13, Slower Eluting Isomer). Example 12 (Faster ElutingIsomer): MS(ESI) m/z: 478.2[M+H]; 1H NMR (400 MHz, CDCl₃): δ=9.16 (s,1H), 9.07 (s, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.15(d, J=8.0 Hz, 1H), 6.90-6.86 (m, 2H), 4.84 (d, J=10.8 Hz, 1H), 3.99 (s,3H), 3.04 (t, J=13.6 Hz, 1H), 2.85-2.79 (m, 2H), 2.52 (d, J=13.6 Hz,3H), 1.94 (t, J=10.0 Hz, 1H), 2.16-1.99 (m, 2H), 1.94 (t, J=10.0 Hz,1H), 1.96-1.75 (m, 1H), 1.11-0.98 (m, 4H), 0.62-0.60 (m, 1H), 0.37-0.36(m, 2H), 0.03-0.02 (m, 1H). Example 13 (Slower Eluting Isomer): MS(ESI)m/z: 478.2[M+H]; 1H NMR (400 MHz, CDCl₃): δ=9.16 (s, 1H), 9.07 (s, 1H),8.18 (d, J=1.6 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H),6.90-6.86 (m, 2H), 4.84 (d, J=10.8 Hz, 1H), 3.99 (s, 3H), 3.04 (t,J=13.6 Hz, 1H), 2.85-2.79 (m, 2H), 2.52 (d, J=13.6 Hz, 3H), 1.94 (t,J=10.0 Hz, 1H), 2.16-1.99 (m, 2H), 1.94 (t, J=10.0 Hz, 1H), 1.96-1.75(m, 1H), 1.11-0.98 (m, 4H), 0.62-0.60 (m, 1H), 0.37-0.36 (m, 2H),0.03-0.02 (m, 1H). Example 12 (faster eluting isomer) and Example 13(slower eluting isomer) may be converted to the sodium salt by thefollowing method. To a solution of Example 12 (92 mg, 0.078 mmol) inMeCN (0.5 mL) was added a solution of NaOH (aq. 172 mg, 0.5 M), themixture was stirred for 1 hour at 20° C. (room temperature). Then thereaction mixture was frozen and lyophilized to give the sodium salt ofExample 12. The sodium salt of Example 13 may be prepared using the samemethod starting with Example 13 (slower eluting isomer).

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

Biological Assays

Generation of GPR40-Expressing Cells:

Human and mouse GPR40 stable cell-lines were generated in CHO cellsstably expressing NFAT BLA (Beta-lactamase). A human GPR40 stablecell-line was generated in HEK cells stably expressing the acquorinexpressing reporter. The expression plasmids were transfected usinglipofectamine (Life Technologies) following manufacturer's instructions.Stable cell-lines were generated following drug selection.

FLIPR Assays:

FLIPR (Fluorimetric Imaging Plate Reader, Molecular Devices) assays wereperformed to measure agonist-induced calcium mobilization of the stableclones. For the FLIPR assay, one day before assay, GPR40/CHO NFAT BLAcells were seeded into black-wall-clear-bottom 384-well plates (Costar)at 1.4×10e4 cells/20 μL medium/well. The cells were incubated with 20μl/well of the assay buffer (HBSS, 0.1% BSA, 20 mM HEPES, 2.5 mMprobenecid, pH 7.4) containing 8 μM fluo-4,AM, 0.08% pluronic acid atroom temperature for 100 minutes. Fluorescence output was measured usingFLIPR. Compounds were dissolved in DMSO and diluted to desiredconcentrations with assay buffer. 13.3 μL/well of compound solution wasadded. The FLIPR Assay EC₅₀ values for specific compounds are listed inTable I.

Inositol Phosphate Turnover (IP1) Assay:

The assay is performed in 384-well format. HEK cells stably expressinghuman GPR40 are plated at 15,000 cells per well in growth medium(DMEM/10% fetal calf serum). Cell plates are then incubated 16 hours at37 degrees in a 5% CO2 incubator.

Measurement of Inositol Phosphate Turnover (IP1) is performed using theCisBio IP-One kit (Part number 62IPAPEB). After the 16 hour incubation,the cells are washed with HEPES buffer and 10 ul of stimulation buffer(prepared as described in the kit) is added to each well. In a separateplate, compounds are diluted in DMSO (400-fold over the finalconcentration in the assay well) and 25 nl is acoustically transferredto the appropriate well in the assay cell plate. The plates are thenincubated for 60 minutes at 37 degrees. 10 ul of detection buffer (alsoprepared as described in the IP-One kit) is added to each well and theplates are incubated for 60 minutes in the dark. The plates are thenread in a Perkin Elmer EnVision or equivalent reader able to measureFRET. Fluorescent ratio of emission at 665 and 620 nm is then convertedto IP1 concentration by back calculating from an IP1 standard curveprepared at the time of the assay. The Inositol Phosphate Turnover (IP1)Assay EC₅₀ values for specific compounds are listed in Table I.

The compounds of the present invention, including the compounds inExamples 1-13, have either EC₅₀ values less than 10 micromolar (μM) inthe FLIPR assay described above, or have EC₅₀ values less than 6500nanomolar (nM) in the Inositol Phosphate Turnover (IP1) Assay describedabove.

TABLE I Example Human FLIPR EC₅₀, nM Human IP1 No. Stereoisomers or %activation Assay, EC50, nM 1 Isomer A^(a) ND 3.6 2 Isomer B^(a) ND 14 3Isomer A^(b) ND 13 4 Isomer B^(b) ND 27 5 Isomer A^(a) ND 3.1 6 IsomerB^(a) ND 5.2 7 Isomer A^(a) ND 3.0 8 Isomer B^(a) ND 29 9 Mix of isomers3300 ND 10 Isomer A^(a) ND 4.6 11 Isomer B^(a) ND 6.0 12 Isomer A^(b) ND116 13 Isomer B^(b) ND 684 *Isomer A = first eluting peak from chiralcolumn; Isomer B = second eluting peak from chiral column; “ND” is notdetermined; ^(a)Isomers separated at methyl ester stage; ^(b)Isomersseparated at carboxylic acid stage.In Vivo Studies:

Male C57BL/6N mice (7-12 weeks of age) are housed 10 per cage and givenaccess to normal diet rodent chow and water ad libitum. Mice arerandomly assigned to treatment groups and fasted 4 to 6 h. Baselineblood glucose concentrations are determined by glucometer from tail nickblood. Animals are then treated orally with vehicle (0.25%methylcellulose) or test compound. Blood glucose concentration ismeasured at a set time point after treatment (t=0 min) and mice are thenintraperitoneally-challenged with dextrose (2 g/kg). One group ofvehicle-treated mice is challenged with saline as a negative control.Blood glucose levels are determined from tail bleeds taken at 20, 40, 60min after dextrose challenge. The blood glucose excursion profile fromt=0 to t=60 min is used to integrate an area under the curve (AUC) foreach treatment. Percent inhibition values for each treatment aregenerated from the AUC data normalized to the saline-challengedcontrols.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of the invention indicated above. The specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

The invention claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein “a” is a singlebond; T is CH; U is CR¹; V is CR²; W is CH; Q is selected from the groupconsisting of: —CR⁴R⁶; X is selected from the group consisting of:—CR⁹R⁹; Y is selected from the group consisting of: —CR⁹R⁹; Z is oxygen;A is selected from the group consisting of: (1) aryl, (2) heteroaryl,(3) C₃₋₆cycloalkyl, and (4) C₂₋₅cycloheteroalkyl, wherein A isunsubstituted or substituted with one to five substituents selected fromR^(a); B is selected from the group consisting of: (1) hydrogen, (2)aryl, (3) aryl-O—, (4) aryl-C₁₋₁₀ alkyl-, (5) aryl-C₁₋₁₀ alkyl-O—, (6)C₃₋₆cycloalkyl, (7) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-, (8)C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—, (9) C₃₋₆cycloalkenyl, (10)C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-, (11) C₃₋₆cycloalkenyl-C₁₋₁₀alkyl-O—, (12)C₂₋₅cycloheteroalkyl, (13) C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-, (14)C₃₋₆cycloheteroalkyl-C₁₋₁₀alkyl-O—, (15) heteroaryl, (16) heteroaryl-O—,(17) heteroaryl-C₁₋₁₀ alkyl-, and (18) heteroaryl-C₁₋₁₀ alkyl-O—,wherein B is unsubstituted or substituted with one to five substituentsselected from R^(b); R¹ and R² are each independently selected from: (1)a bond, (2) hydrogen, (3) halogen, (4) —OR^(k), (5) —CN, (6) —C₁₋₆alkyl,(7) —C₃₋₆cycloalkyl, (8) —C₃₋₆cycloalkyl-C₁₋₃alkyl-, (9)—C₂₋₆cycloheteroalkyl, and (10) —C₂₋₆cycloheteroalkyl-C₁₋₃alkyl-,wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with a substituent selected fromR⁷, or R¹ and R² together with the atom(s) to which they are attachedform a C₃₋₆cycloalkyl ring or a C₂₋₅cycloheteroalkyl ring containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN-Rg, wherein each R¹ and R² is unsubstituted or substituted with one tothree substituents selected from R^(L), and wherein one of R¹ and R² issubstituted with a substituent selected from R⁷; R³ is absent orselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—OR^(e), (4) —CN, (5) —C₁₋₆alkyl, (6) —C₃₋₆cycloalkyl, and (7)—C₃₋₆cycloalkyl-C₁₋₃alkyl-, wherein each alkyl and cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(i); R⁴ is selected from the group consisting of: (1) hydrogen,(2) halogen, (3) OR^(e), (4) C₀₋₅alkylNR^(c)R^(d), (5) C₁₋₆alkyl, (6)C₁₋₆alkyl-O—, (7) C₃₋₆cycloalkyl, (8) C₃₋₆cycloalkyl-O—, (9)C₃₋₆cycloalkyl-C₁₋₁₀alkyl-, (10) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-O—, (11)C₂₋₅cycloheteroalkyl, (12) C₂₋₅cycloheteroalkyl-O—, (13)C₂₋₅cycloheteroalkyl-C₁₋₁₀ alkyl-, (14) C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-O—, (15) aryl, (16) aryl-O—, (17) aryl-C₁₋₁₀alkyl-, (18)heteroaryl, (19) heteroaryl-O—, and (20) heteroaryl-C₁₋₁₀alkyl-, whereineach alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituents selectedfrom R^(j); R⁵ is selected from the group consisting of: (1) hydrogen,(2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(j); R⁶ is selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl,wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(j); R⁷ is selected from thegroup consisting of: (1) —CO₂R⁸, (2) —C₁₋₆alkyl-CO₂R⁸, (3)—C₁₋₆alkyl-CONHSO₂R^(m), (4) —C₁₋₆alkyl-SO₂NHCOR^(m), (5)—C₁₋₆alkyl-tetrazolyl, and (6) a cycloheteroalkyl selected from thegroup consisting of:

R⁸ is selected from the group consisting of: (1) hydrogen, (2)—C₁₋₆alkyl, (3) —C₃₋₆cycloalkyl, and (4) aryl-C₁₋₆alkyl, wherein eachalkyl, cycloalkyl and aryl is unsubstituted or substituted with one tothree substituents selected from R^(j); R⁹ is selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) halogen, (4)—(CH₂)₀₋₅OH, (5) —(CH₂)₀₋₅ OC₁₋₆alkyl, (6) —(CH₂)₀₋₅ NR^(c)R^(d), (7)—C₃₋₆cycloalkyl, and (8) aryl-C₁₋₆alkyl, wherein each CH₂, alkyl,cycloalkyl and aryl is unsubstituted or substituted with one to threesubstituents selected from R^(j); R^(a) is selected from the groupconsisting of: (1) —C₁₋₆alkyl, (2) halogen, (3) —C₀₋₆alkyl-OR^(e), (4)—C₀₋₆alkyl-NR^(c)S(O)_(n)R^(e), (5) —C₀₋₆alkyl-S(O)_(n)R^(e), (6)—C₀₋₆alkyl-S(O)_(n)NR^(c)R^(d), (7) —C₀₋₆alkyl-NR^(c)R^(d), (8)—C₀₋₆alkyl-C(O)R^(e), (9) —C₀₋₆alkyl-OC(O)R^(e), (10)—C₀₋₆alkyl-CO₂R^(e), (11) —C₀₋₆alkyl-CN, (12)—C₀₋₆alkyl-C(O)NR^(c)R^(d), (13) —C₀₋₆alkyl-NR^(c)C(O)R^(e), (14)—C₀₋₆alkyl-NR^(c)C(O)OR^(e), (15) —C₀₋₆alkyl-NR^(c)C(O)NR^(c)R^(d), (16)—CF₃, (17) —OCF₃, (18) —OCHF₂, (19) —C₀₋₆alkyl-aryl, (20)—C₀₋₆alkyl-heteroaryl, (21) —C₀₋₆alkyl-C₃₋₁₀cycloalkyl, (22)—C₀₋₆alkyl-C₃₋₁₀cycloalkenyl, and (23) —C₀₋₆alkyl-C₂₋₁₀cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to five substituents independently selected from: —C₁₋₆alkyl,halogen, OH, —O—C₁₋₆alkyl, —S(O)₂—C₁₋₄alky, —CN, —OCHF₂, —OCF₃, —CF₃,and —C₀₋₆alkyl-NR^(c)R^(d); R^(b) is independently selected from thegroup consisting of: (1) —C₁₋₁₀alkyl, (2) —C₂₋₁₀alkenyl, (3) —CF₃, (4)halogen, (5) —CN, (6) —OH, (7) —OC₁₋₁₀alkyl, (8) —OC₂₋₁₀alkenyl, (9)—O(CH₂)_(p)OC₁₋₁₀alkyl, (10) —O(CH₂)_(p)C₃₋₆cycloalkyl, (11)—O(CH₂)_(p)C₃₋₆cycloalkyl-C₁₋₁₀alkyl-, (12)—O(CH₂)_(p)C₂₋₅cycloheteroalkyl, (13)—O(CH₂)_(p)C₂₋₅cyclohereroalkyl-C₁₋₁₀alkyl-, (14) —O-aryl, (15)—O-heteroaryl, (16) —O-aryl-C₁₋₁₀alkyl-, (17) —O-heteroaryl-C₁₋₁₀alkyl-,(18) —O(CH₂)_(p)NR^(c)S(O)_(m)R^(e), (19) —O(CH₂)_(p)S(O)_(m)R^(e), (20)—O(CH₂)_(p)S(O)_(m)NR^(c)R^(d), (21) —O(CH₂)_(p)NR^(c)R^(d), (22)—C(O)R^(e), (23) —OC(O)R^(e), (24) —CO₂R^(e), (25) —C(O)NR^(c)R^(d),(26) —NR^(c)C(O)R^(e), (27) —NR^(c)C(O)OR^(e), (28)—NR^(c)C(O)NR^(c)R^(d), (29) —O(CH₂)_(p)O—C₃₋₆cycloalkyl, (30)—O(CH₂)_(p)O—C₂₋₅cycloheteroalkyl, (31) —OCF₃, (32) —OCHF₂, (33)—(CH₂)_(p)C₃₋₆cycloalkyl, (34) —(CH₂)_(p)C₂₋₅cycloheteroalkyl, (35)aryl, (36) heteroaryl, (37) aryl-C₁₋₁₀alkyl-, and (38)heteroaryl-C₁₋₁₀alkyl-, wherein each CH, CH₂, alkyl, alkenyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to five substituents independently selected from:—C₁₋₆alkyl, halogen, OH, —O—C₁₋₆alkyl and —CF₃; R^(c) and R^(d) are eachindependently selected from the group consisting of: (1) hydrogen, (2)C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₃₋₆cycloalkyl, (5) C₃₋₆cycloalkyl-C₁₋₁₀alkyl-, (6) C₂₋₅cycloheteroalkyl, (7)C₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl-, (8) aryl, (9) heteroaryl, (10)aryl-C₁₋₁₀alkyl-, and (11) heteroaryl-C₁₋₁₀alkyl-, wherein each alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from R^(f), or R^(c) and R^(d) together with theatom(s) to which they are attached form a C₂₋₁₀ cycloheteroalkyl ringcontaining 0-2 additional heteroatoms independently selected fromoxygen, sulfur and N—R^(g), wherein each R^(c) and R^(d) isunsubstituted or substituted with one to three substituentsindependently selected from R^(f); each R^(e) is independently selectedfrom the group consisting of: (1) hydrogen, (2) —C₁₋₁₀alkyl, (3)—C₂₋₁₀alkenyl, (4) —C₃₋₆ cycloalkyl, (5) —C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-,(6) —C₂₋₅cycloheteroalkyl, (7) —C₂₋₅cycloheteroalkyl-C₁₋₁₀alkyl-, (8)aryl, (9) aryl-C₁₋₁₀alky-, (10) heteroaryl, and (11)heteroaryl-C₁₋₁₀alkyl-, wherein each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to three substituents selected from R^(h); each R^(f) isselected from the group consisting of: (1) halogen, (2) C₁₋₁₀alkyl, (3)—OH, (4) —O—C₁₋₄alkyl, (5) —S(O)_(m)-C₁₋₄alkyl, (6) —CN, (7) —CF₃, (8)—OCHF₂, and (9) —OCF₃, wherein each alkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, C₁₋₆alkyl, cyano and S(O)₂C₁₋₆alkyl; each R^(g) isselected from the group consisting of: (1) hydrogen, (2) —C(O)R^(e), and(3) —C₁₋₁₀alkyl, wherein each alkyl is unsubstituted or substituted withone to five halogens; each R^(h) is selected from the group consistingof: (1) halogen, (2) C₁₋₁₀alkyl, (3) —OH, (4) —O—C₁₋₄alkyl, (5)—S(O)_(m)—C₁₋₄alkyl, (6) —CN, (7) —CF₃, (8) —OCHF₂, and (9) —OCF₃,wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, C₁₋₆alkyl, cyanoand S(O)₂C₁₋₆alkyl; R^(i) is independently selected from the groupconsisting of: (1) —C₁₋₆alkyl, (2) —OR^(e), (3) —NR^(c)S(O)_(m)R^(e),(4) halogen, (5) —S(O)_(m)R^(e), (6) —S(O)_(m)NR^(c)R^(d), (7)—NR^(c)R^(d), (8) —C(O)R^(e), (9) —OC(O)R^(e), (10) —CO₂R^(e), (11) —CN,(12) —C(O)NR^(c)R^(d), (13) —NR^(c)C(O)R^(e), (14) —NR^(c)C(O)OR^(e),(15) —NR^(c)C(O)NR^(c)R^(d), (16) —CF₃, (17) —OCF₃, (18) —OCHF₂, (19)—C₃₋₆cycloalkyl, and (20) —C₂₋₅cycloheteroalkyl; R^(j) is independentlyselected from the group consisting of: (1) —C₁₋₆alkyl, (2) —OR^(e), (3)—NR^(c)S(O)_(m)R^(e), (4) halogen, (5) —S(O)_(m)R^(e), (6)—S(O)_(m)NR^(c)R^(d), (7) —NR^(c)R^(d), (8) —C(O)R^(e), (9) —OC(O)R^(e),(10) —CO₂R^(e), (11) —CN, (12) —C(O)NR^(c)R^(d), (13) —NR^(c)C(O)R^(e),(14) —NR^(c)C(O)OR^(e), (15) —NR^(c)C(O)NR^(c)R^(d), (16) —CF₃, (17)—OCF₃, (18) —OCHF₂, (19) —C₃₋₆cycloalkyl, and (20) —₂₋₅cycloheteroalkyl;each R^(k) is independently selected from the group consisting of: (1)hydrogen, (2) —C₁₋₆ alkyl, (3) —C₁₋₆alkyl-SO₂C₁₋₆alkyl, (4) —CF₃, and(5) —CHF₂, wherein each alkyl is unsubstituted or substituted with oneto three substituents independently selected from: —OH, —OC₁₋₆alkyl,halogen, cyano, and —S(O)₂C₁₋₆alkyl; each R^(L) is independentlyselected from the group consisting of: (1) —CO₂C₁₋₆alkyl, (2)—C₁₋₁₀alkyl, (3) —C₂₋₁₀ alkenyl, (4) —C₂ ₋₁₀alkynyl, (5)—C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) aryl, and (8)heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to four substituents independently selected from C₁₋₆alkyl,halogen, and —OC₁₋₆alkyl; each R^(m) is independently selected from thegroup consisting of: (1) —C₁₋₁₀alkyl, (2) —C₂₋₁₀ alkenyl, (3) —C₃₋₆cycloalkyl, (4) —C₃₋₆ cycloalkyl-C₁₋₁₀alkyl-, (5) —C₂₋₅cycloheteroalkyl,(6) —C₂₋₅ cycloheteroalkyl-C₁₋₁₀alkyl-, (7) aryl, (8) heteroaryl, (9)aryl-C₁₋₁₀alkyl-, and (10) heteroaryl-C₁₋₁ ₀alkyl-; each n isindependently selected from: 0, 1 or 2; each m is independently selectedfrom: 0, 1 or 2; each p is independently selected from: 0, 1, 2, 3, 4, 5or 6; and each r is independently selected from: 0, 1, 2 or
 3. 2. Thecompound according to claim 1 wherein A is selected from the groupconsisting of: (1) aryl, (2) heteroaryl, and (3) C₂₋₅cycloheteroalkyl,wherein each aryl, heteroaryl and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(a); or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 wherein A is selected from the group consisting of: (1) phenyl,(2) pyridyl, and (3) azetidine, wherein each phenyl, pyridyl andazetidine is unsubstituted or substituted with one to five substituentsselected from R^(a); or a pharmaceutically acceptable salt thereof. 4.The compound according to claim 1 wherein B is selected from the groupconsisting of: (1) aryl, (2) aryl-C₁₋₁₀ alkyl-, and (3) heteroaryl,wherein each alkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to five substituents selected from R^(b); or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1 wherein Bis selected from the group consisting of: (1) phenyl, (2) —CH₂-phenyl,and (3) pyridyl, wherein each phenyl and pyridyl is unsubstituted orsubstituted with one to five substituents selected from R^(b); or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1 wherein R¹ and R² are each independently selected from: (1)hydrogen, and (2) —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with a substituent selected fromR⁷; or a pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 1 wherein R¹ and R² are each independently selectedfrom: (1) hydrogen, and (2) —C₂alkyl, wherein each alkyl isunsubstituted or substituted with one to three substituents selectedfrom R^(L), and wherein one of R¹ and R² is substituted with asubstituent selected from R⁷; or a pharmaceutically acceptable saltthereof.
 8. The compound according to claim 1 wherein R³ is absent orhydrogen; R⁴ is hydrogen; R⁵ is hydrogen; and R⁶ is hydrogen; or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1 wherein R⁷ is —CO₂R⁸; or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 1 wherein R⁸ is hydrogen;or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 1 wherein R⁹ is hydrogen; or a pharmaceuticallyacceptable salt thereof.
 12. The compound according to claim 1 ofstructural Formula Ia:

wherein “a” is a single bond; Q is selected from the group consistingof: —CR⁴R⁶; X is selected from the group consisting of: —CR⁹R⁹; Y isselected from the group consisting of: —CR⁹R⁹; Z is oxygen; A isselected from the group consisting of: (1) aryl, (2) heteroaryl, and (3)C₂₋₅cycloheteroalkyl, wherein each aryl, heteroaryl and cycloheteroalkylis unsubstituted or substituted with one to five substituents selectedfrom R^(a); B is selected from the group consisting of: (1) aryl, (2)aryl-C₁₋₁₀ alkyl-, and (3) heteroaryl, wherein each alkyl, aryl andheteroaryl is unsubstituted or substituted with one to five substituentsselected from R^(b); R¹ and R² are each independently selected from: (1)hydrogen, and (2) —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to three substituents selected from R^(L), andwherein one of R¹ and R² is substituted with a substituent selected fromR⁷; R³ is absent or hydrogen; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ ishydrogen; R⁷ is —CO₂R⁸; R⁸ is hydrogen; R⁹ is hydrogen; each R^(L) isindependently selected from the group consisting of: —C₁₋₁₀alkyl, and-C₃₋₆cycloalkyl, wherein each alkyl, and cycloalkyl is unsubstituted orsubstituted with one to four substituents independently selected fromC₁₋₆alkyl, halogen, and —OC₁₋₆alkyl; and each r is independentlyselected from: 0, 1, 2 or 3; or a pharmaceutically acceptable saltthereof.
 13. The compound according to claim 1 of structural Formula Ia:

wherein “a” is a single bond; Q is selected from the group consistingof: —CR⁴R⁶; X is selected from the group consisting of: —CR⁹R⁹; Y isselected from the group consisting of: —CR⁹R⁹; Z is oxygen; A isselected from the group consisting of: (1) phenyl, (2) pyridyl, and (3)azetidine, wherein each phenyl, pyridyl and azetidine is unsubstitutedor substituted with one to five substituents selected from R^(a); B isselected from the group consisting of: (1) phenyl, (2) —CH₂-phenyl, and(3) pyridyl, wherein each phenyl and pyridyl is unsubstituted orsubstituted with one to five substituents selected from R^(b); R¹ and R²are each independently selected from: (1) hydrogen, and (2) —C₂alkyl,wherein each alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(L), and wherein one of R¹ and R² issubstituted with a substituent selected from R⁷; R³ is absent orhydrogen; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is hydrogen; R⁷ is —CO₂R⁸;R⁸ is hydrogen; R⁹ is hydrogen; each R^(L) is independently selectedfrom the group consisting of: —CH₃, and —cyclopropyl; and each r isindependently selected from: 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof.
 14. The compound according to claim 13 selectedfrom:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 16.A method of treating type 2 diabetes mellitus in a patient in need oftreatment comprising the administration to the patient of atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.